Structural Virology: The Key Determinants in Development of Antiviral Therapeutics
Abstract
:1. Introduction
2. Exploring the 3D Protein Landscape: Structural Biology Techniques
2.1. X-Ray Crystallography
2.2. Nuclear Magnetic Resonance (NMR)
2.3. Transmission Electron Microscopy (TEM)
2.4. Cryo-Electron Microscopy (Cryo-EM)
2.5. Small Angle X-Ray Scattering (SAXS)
2.6. Cryo-Electron Tomography (Cryo-ET)
2.7. Emerging Techniques
3. Exploring Viral Structural Proteins
3.1. Envelope Glycoproteins
3.2. Viroporins
3.3. Capsid
4. Exploring Viral Non-Structural Proteins
4.1. Protease
4.2. Polymerase
4.3. Integrase
4.4. Thymidine Kinase (TK)
4.5. Methyltransferase (MTase)
4.6. Helicases
5. Host-Targeted Antivirals
6. Rational Drug Design
De Novo Designing—A Targeted Approach with Improved Features
7. Identifying the Threat of Future—A Structural Approach
8. Conclusions and Future Direction
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
3CLpro | 3-chymotrypsin-like proteases |
3D | Three-dimensional |
3-P | 3′-processing |
3TC | Lamivudine |
5-CITEP | 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)propenone |
ABT | ABT199/venetoclax |
ACE2 | Angiotensin-converting enzyme 2 |
ACV | Acyclovir |
ACV | Acyclovir |
ADE | Antibody-dependent enhancement |
AI | Artificial Intelligence |
ALLINI | Allosteric IN inhibitors |
APV | Amprenavir |
ART | Antiretroviral therapy |
ASV | Asunaprevir |
ATV | Atazanavir |
BH | Berbamine hydrochloride |
BIC | Bictegravir |
BOC | Boceprevir |
BVDU | Brivudine |
BXA | Baloxavir |
CAPE | Caffeic acid phenethyl ester |
CAR | Coxsackievirus and Adenovirus Receptor |
cART | Combination antiretroviral therapy |
CCR5 | C-C chemokine receptor type 5 |
CD4 | Cluster of differentiation 4 |
CEN | Cap-dependent endonuclease |
CHIKV | Chikungunya Virus |
CLR | C-type lectin receptor |
CMV | Cucumber Mosaic Virus |
COVID-19 | Coronavirus disease 2019 |
CRISPR | Clustered Regularly Interspaced Short Palindromic Repeats |
cryo-EM | Cryo-electron microscopy |
Cryo-ET | Cryo-electron tomography |
CsA | Cyclosporin A |
CVB4 | Coxsackie B4 virus |
CXCR4 | C-X-C chemokine receptor type 4 |
Cyp | Cyclophilin |
d4T | Stavudine |
DC-SIGN | Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin |
DdDp | DNA-Dependent DNA Polymerase |
DdRp | DNA-Dependent RNA Polymerase |
DENV | Dengue Virus |
DKA | Diketoacid |
DLV | Delavirdine |
DNA | Deoxyribonucleic Acid |
DOR | Doravirine |
DPV | Dapivirine |
DRV | Darunavir |
dT | Deoxythymidine |
DTG | Dolutegravir |
EFV | Efavirenz |
ENS | Ensitrelvir |
ETR | Etravirine |
EUA | Emergency use authorization |
FDA | Food and Drug Administration |
FVP | Favipiravir |
G3BP1 | Ras GTPase-activating protein SH3-domain-binding protein 1 |
GLE | Glecaprevir |
GTase | m7GTP transferase |
GV | Giant viruses |
GZR | Grazoprevir |
HA | hemagglutinin |
HBV | Hepatitis B Virus |
HC | Herbacetin |
HCoV | Human Coronavirus- |
HCV | Hepatitis C Virus |
HHV | Human Herpesvirus |
HIV | Human Immunodeficiency Virus |
HPV | Human Papillomavirus |
HS | heparan sulfate |
HTLV | Human T-Cell Leukemia Virus |
IBD | Integrase binding domain |
ICTV | International Committee on Taxonomy of Viruses |
IDP | Intrinsically disordered proteins |
IDR | Intrinsically disordered regions |
IDU | Idoxuridine |
IDV | Indinavir |
IFN | Interferon |
IFN | Interferon |
IL-10 | Interleukin 10 |
IN | Integrase |
INSTI | Integrase strand transfer inhibitors |
INT | Intasome |
IQM | Imiquimod |
IR | Infrared |
ISG | Interferon-Stimulated Genes |
KSHV | Kaposi‘s Sarcoma-Associated Herpesvirus |
LEDGF/p75 | Lens Epithelium-Derived Growth Factor/p75 |
LPV | Lopinavir |
MCV or MCPyV | Merkel Cell Polyomavirus |
MD | Molecular Dynamics |
MERS-CoV | Middle East respiratory syndrome coronavirus |
MINI | Multimerization-selective integrase inhibitor |
MOV | Molnupiravir |
Mpro | Main protease |
MPXV | Monkeypox virus |
MTase | Methyltransferase |
MXRA8 | Matrix remodeling-associated protein 8 |
NA | Neuraminidase |
NFV | Nelfinavir |
NiRAN | RdRp-associated nucleotidyltransferase |
NMR | Nuclear Magnetic Resonance |
NMV | Nirmatrelvir |
NNRTI | Non-nucleoside reverse transcriptase inhibitors |
NRTI | Nucleoside reverse transcriptase inhibitors |
NTD | N-terminal domain |
NTD | N-terminal domain |
NTP | Nucleoside triphosphate |
NVP | Nevirapine |
PCV | Penciclovir |
PDX | Podofilox |
PFA | Foscarnet |
PI | Peptide inhibitors |
PIC | Pre-integration complex |
PLpro | Papain-like protease |
PPI | Protein–protein interactions |
PRF | Programmed ribosomal frameshifting |
PT | Ponatinib |
PVY | Potato Virus Y |
RABV | Rabies Virus |
RBD | Receptor-binding domain |
RdRp | RNA-Dependent RNA Polymerase |
RDV | Remdesivir |
RNA | Ribonucleic Acid |
RNase | Ribonuclease |
RNP | Ribonucleoprotein |
RPV | Rilpivirine |
RSV | Respiratory syncytial virus |
RT | Reverse Transcriptase |
RTV | Ritonavir |
RV | Rotavirus |
SAH | S-adenosyl homocysteine |
SAM | S-adenosyl-l-methionine |
SARS-CoV | Severe Acute Respiratory Syndrome Coronavirus |
SARS-CoV-2 | Severe Acute Respiratory Syndrome Coronavirus 2 |
SAXS | Small Angle X-ray Scattering |
SBDD | Structure-based drug design |
SERM | Selective estrogen receptor modulators |
SG | Stress granule |
SINE | Sinecatechins |
SINV | Sindbis Virus |
SMV | Simeprevir |
SQV | Saquinavir |
ST | Strand transfer |
TBSV | Tomato bushy stunt virus |
TDF | Tenofovir disoproxil fumarate |
TEM | Transmission electron microscopy |
TK | Thymidine kinase |
TMV | Tobacco Mosaic Virus |
TPV | Tipranavir |
TVR | Telaprevir |
VEEV | Venezuelan Equine Encephalitis virus |
VLP | Virus-like particle |
VOX | Voxilaprevir |
VPV | Vaniprevir |
VZV | Varicella-zoster virus |
WHO | World Health Organization |
XFEL | X-ray Free Electron Laser |
XRD | X-ray diffraction |
References
- Payne, S. Introduction to Animal Viruses. In Viruses; Elsevier: Amsterdam, The Netherlands, 2017; pp. 1–11. [Google Scholar]
- Current ICTV Taxonomy Release|ICTV. Available online: https://ictv.global/taxonomy (accessed on 27 December 2024).
- Wirth, J.; Young, M. The Intriguing World of Archaeal Viruses. PLoS Pathog. 2020, 16, e1008574. [Google Scholar] [CrossRef]
- Krupovic, M.; Cvirkaite-Krupovic, V.; Iranzo, J.; Prangishvili, D.; Koonin, E.V. Viruses of Archaea: Structural, Functional, Environmental and Evolutionary Genomics. Virus Res. 2018, 244, 181–193. [Google Scholar] [CrossRef] [PubMed]
- Mahler, M.; Costa, A.R.; van Beljouw, S.P.B.; Fineran, P.C.; Brouns, S.J.J. Approaches for Bacteriophage Genome Engineering. Trends Biotechnol. 2023, 41, 669–685. [Google Scholar] [CrossRef] [PubMed]
- Gordillo Altamirano, F.L.; Barr, J.J. Phage Therapy in the Postantibiotic Era. Clin. Microbiol. Rev. 2019, 32, e00066-18. [Google Scholar] [CrossRef] [PubMed]
- Queiroz, V.F.; Tatara, J.M.; Botelho, B.B.; Rodrigues, R.A.L.; Almeida, G.M.d.F.; Abrahao, J.S. The Consequences of Viral Infection on Protists. Commun. Biol. 2024, 7, 306. [Google Scholar] [CrossRef]
- Kalafati, E.; Papanikolaou, E.; Marinos, E.; Anagnou, N.P.; Pappa, K.I. Mimiviruses: Giant viruses with novel and intriguing features. Mol. Med. Rep. 2022, 25, 207. [Google Scholar] [CrossRef]
- Coy, S.R.; Gann, E.R.; Pound, H.L.; Short, S.M.; Wilhelm, S.W. Viruses of Eukaryotic Algae: Diversity, Methods for Detection, and Future Directions. Viruses 2018, 10, 487. [Google Scholar] [CrossRef]
- Hough, B.; Steenkamp, E.; Wingfield, B.; Read, D. Fungal Viruses Unveiled: A Comprehensive Review of Mycoviruses. Viruses 2023, 15, 1202. [Google Scholar] [CrossRef]
- Jones, R.A.C.; Janssen, D. Global Plant Virus Disease Pandemics and Epidemics. Plants 2021, 10, 233. [Google Scholar] [CrossRef]
- Tatineni, S.; Hein, G.L. Plant Viruses of Agricultural Importance: Current and Future Perspectives of Virus Disease Management Strategies. Phytopathology 2023, 113, 117–141. [Google Scholar] [CrossRef]
- Bertola, M.; Mutinelli, F. A Systematic Review on Viruses in Mass-reared Edible Insect Species. Viruses 2021, 13, 2280. [Google Scholar] [CrossRef] [PubMed]
- Garrison, A.R.; Alkhovsky, S.V.; Avšič-Županc, T.; Bente, D.A.; Bergeron, É.; Burt, F.; Paola, N.D.; Ergünay, K.; Hewson, R.; Kuhn, J.H.; et al. ICTV Virus Taxonomy Profile: Nairoviridae. J. Gen. Virol. 2020, 101, 798–799. [Google Scholar] [CrossRef]
- Simmonds, P.; Becher, P.; Bukh, J.; Gould, E.A.; Meyers, G.; Monath, T.; Muerhoff, S.; Pletnev, A.; Rico-Hesse, R.; Smith, D.B.; et al. ICTV Virus Taxonomy Profile: Flaviviridae. J. Gen. Virol. 2017, 98, 2–3. [Google Scholar] [CrossRef] [PubMed]
- Bolling, B.G.; Weaver, S.C.; Tesh, R.B.; Vasilakis, N. Insect-Specific Virus Discovery: Significance for the Arbovirus Community. Viruses 2015, 7, 4911–4928. [Google Scholar] [CrossRef]
- Javanian, M.; Barary, M.; Ghebrehewet, S.; Koppolu, V.; Vasigala, V.K.R.; Ebrahimpour, S. A Brief Review of Influenza Virus Infection. J. Med. Virol. 2021, 93, 4638–4646. [Google Scholar] [CrossRef]
- Hutchinson, E.C. Influenza Virus. Trends Microbiol. 2018, 26, 809–810. [Google Scholar] [CrossRef]
- Brunker, K.; Mollentze, N. Rabies Virus. Trends Microbiol. 2018, 26, 886–887. [Google Scholar] [CrossRef] [PubMed]
- Li, G.; Hilgenfeld, R.; Whitley, R.; De Clercq, E. Therapeutic Strategies for COVID-19: Progress and Lessons Learned. Nat. Rev. Drug Discov. 2023, 22, 449–475. [Google Scholar] [CrossRef]
- Ciotti, M.; Ciccozzi, M.; Terrinoni, A.; Jiang, W.C.; Wang, C.B.; Bernardini, S. The COVID-19 Pandemic. Crit. Rev. Clin. Lab. Sci. 2020, 365–388. [Google Scholar] [CrossRef]
- Crimi, S.; Fiorillo, L.; Bianchi, A.; D’amico, C.; Amoroso, G.; Gorassini, F.; Mastroieni, R.; Marino, S.; Scoglio, C.; Catalano, F.; et al. Herpes Virus, Oral Clinical Signs and QoL: Systematic Review of Recent Data. Viruses 2019, 11, 463. [Google Scholar] [CrossRef]
- Rechenchoski, D.Z.; Faccin-Galhardi, L.C.; Linhares, R.E.C.; Nozawa, C. Herpesvirus: An Underestimated Virus. Folia Microbiol. 2017, 62, 151–156. [Google Scholar] [CrossRef] [PubMed]
- Connolly, S.A.; Jardetzky, T.S.; Longnecker, R. The Structural Basis of Herpesvirus Entry. Nat. Rev. Microbiol. 2020, 19, 110–121. [Google Scholar] [CrossRef]
- Agut, H.; Bonnafous, P.; Gautheret-Dejean, A. Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections. Clin. Microbiol. Rev. 2015, 28, 313–335. [Google Scholar] [CrossRef] [PubMed]
- de Sanjosé, S.; Brotons, M.; Pavón, M.A. The Natural History of Human Papillomavirus Infection. Best Pract. Res. Clin. Obstet. Gynaecol. 2018, 47, 2–13. [Google Scholar] [CrossRef] [PubMed]
- Burd, E.M.; Dean, C.L. Human Papillomavirus. In Diagnostic Microbiology of the Immunocompromised Host; ASM Press: Washington, DC, USA, 2016; pp. 177–195. [Google Scholar] [CrossRef]
- Schiffman, M.; Doorbar, J.; Wentzensen, N.; De Sanjosé, S.; Fakhry, C.; Monk, B.J.; Stanley, M.A.; Franceschi, S. Carcinogenic Human Papillomavirus Infection. Nat. Rev. Dis. Primers 2016, 2, 1–20. [Google Scholar] [CrossRef]
- Yoshimura, K. Current Status of HIV/AIDS in the ART Era. J. Infect. Chemother. 2017, 23, 12–16. [Google Scholar] [CrossRef]
- Bekker, L.G.; Beyrer, C.; Mgodi, N.; Lewin, S.R.; Delany-Moretlwe, S.; Taiwo, B.; Masters, M.C.; Lazarus, J.V. HIV Infection. Nat. Rev. Dis. Primers 2023, 9, 1–21. [Google Scholar] [CrossRef]
- Lévêque, N.; Semler, B.L. A 21st Century Perspective of Poliovirus Replication. PLoS Pathog. 2015, 11, e1004825. [Google Scholar] [CrossRef]
- Marzi, A.; Blanco, J.R.; Gibellini, D.; Mbani, C.J.; Pandoua Nekoua, M.; Moukassa, D.; Hober, D. The Fight against Poliovirus Is Not Over. Microorganisms 2023, 11, 1323. [Google Scholar] [CrossRef]
- Cao, J.; Li, D. Searching for Human Oncoviruses: Histories, Challenges, and Opportunities. J. Cell Biochem. 2018, 119, 4897–4906. [Google Scholar] [CrossRef]
- Noguera, Z.L.P.; Charypkhan, D.; Hartnack, S.; Torgerson, P.R.; Rüegg, S.R. The Dual Burden of Animal and Human Zoonoses: A Systematic Review. PLoS Negl. Trop. Dis. 2022, 16, e0010540. [Google Scholar] [CrossRef] [PubMed]
- Zeller, M.A.; Carnevale de Almeida Moraes, D.; Ciacci Zanella, G.; Souza, C.K.; Anderson, T.K.; Baker, A.L.; Gauger, P.C. Reverse Zoonosis of the 2022–2023 Human Seasonal H3N2 Detected in Swine. npj Viruses 2024, 2, 1–12. [Google Scholar] [CrossRef]
- Lv, J.X.; Liu, X.; Pei, Y.Y.; Song, Z.G.; Chen, X.; Hu, S.J.; She, J.L.; Liu, Y.; Chen, Y.M.; Zhang, Y.Z. Evolutionary Trajectory of Diverse SARS-CoV-2 Variants at the Beginning of COVID-19 Outbreak. Virus Evol. 2024, 10, veae020. [Google Scholar] [CrossRef]
- Piret, J.; Boivin, G. Pandemics Throughout History. Front. Microbiol. 2021, 11, 631736. [Google Scholar] [CrossRef] [PubMed]
- Taubenberger, J.K.; Morens, D.M. Influenza: The Once and Future Pandemic. Public Health Rep. 2010, 125, 15–26. [Google Scholar] [CrossRef]
- Eisinger, R.W.; Fauci, A.S. Ending the HIV/AIDS Pandemic. Emerg. Infect. Dis. 2018, 24, 413. [Google Scholar] [CrossRef]
- De Cock, K.M.; Jaffe, H.W.; Curran, J.W. Reflections on 40 Years of AIDS. In Advances in Clinical Immunology, Medical Microbiology, COVID-19, and Big Data; Jenny Stanford Publishing: Singapore, 2021; pp. 231–245. [Google Scholar] [CrossRef]
- Chan-Yeung, E.M.; Xu, R.; Chan-Yeung, M.; Chan-yeung, M. SARS: Epidemiology. Respirology 2003, 8, S9–S14. [Google Scholar] [CrossRef]
- Raj, V.S.; Osterhaus, A.D.M.E.; Fouchier, R.A.M.; Haagmans, B.L. MERS: Emergence of a Novel Human Coronavirus. Curr. Opin. Virol. 2014, 5, 58–62. [Google Scholar] [CrossRef]
- Saha, A.; Choudhary, S.; Walia, P.; Kumar, P.; Tomar, S. Transformative Approaches in SARS-CoV-2 Management: Vaccines, Therapeutics and Future Direction. Virology 2025, 604, 110394. [Google Scholar] [CrossRef]
- Listings of WHO’s Response to COVID-19. Available online: https://www.who.int/news/item/29-06-2020-covidtimeline (accessed on 27 December 2024).
- Duggan, A.T.; Perdomo, M.F.; Piombino-Mascali, D.; Marciniak, S.; Poinar, D.; Emery, M.V.; Buchmann, J.P.; Duchêne, S.; Jankauskas, R.; Humphreys, M.; et al. 17th Century Variola Virus Reveals the Recent History of Smallpox. Curr. Biol. 2016, 26, 3407–3412. [Google Scholar] [CrossRef] [PubMed]
- Bandyopadhyay, A.S.; Garon, J.; Seib, K.; Orenstein, W.A. Polio Vaccination: Past, Present and Future. Future Microbiol. 2015, 10, 791–808. [Google Scholar] [CrossRef] [PubMed]
- Jacob, S.T.; Crozier, I.; Fischer, W.A.; Hewlett, A.; Kraft, C.S.; de La Vega, M.A.; Soka, M.J.; Wahl, V.; Griffiths, A.; Bollinger, L.; et al. Ebola Virus Disease. Nat. Rev. Dis. Primers 2020, 6, 13. [Google Scholar] [CrossRef]
- Guo, C.; Zhou, Z.; Wen, Z.; Liu, Y.; Zeng, C.; Xiao, D.; Ou, M.; Han, Y.; Huang, S.; Liu, D.; et al. Global Epidemiology of Dengue Outbreaks in 1990–2015: A Systematic Review and Meta-Analysis. Front. Cell Infect. Microbiol. 2017, 7, 275966. [Google Scholar] [CrossRef]
- Douam, F.; Ploss, A. Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe. Trends Microbiol. 2018, 26, 913–928. [Google Scholar] [CrossRef] [PubMed]
- Baud, D.; Gubler, D.J.; Schaub, B.; Lanteri, M.C.; Musso, D. An Update on Zika Virus Infection. Lancet 2017, 390, 2099–2109. [Google Scholar] [CrossRef]
- Perry, R.T.; Halsey, N.A. The Clinical Significance of Measles: A Review. J. Infect. Dis. 2004, 189, S4–S16. [Google Scholar] [CrossRef]
- Weibel Galluzzo, C.; Kaiser, L.; Chappuis, F. Reemergence of Chikungunya Virus. Rev. Med. Suisse 2015, 11, 1012–1016. [Google Scholar] [CrossRef]
- Turtle, L.; Solomon, T. Japanese Encephalitis—The Prospects for New Treatments. Nat. Rev. Neurol. 2018, 14, 298–313. [Google Scholar] [CrossRef]
- Campbell, G.L.; Marfin, A.A.; Lanciotti, R.S.; Gubler, D.J. West Nile Virus. Lancet Infect. Dis. 2002, 2, 519–529. [Google Scholar] [CrossRef]
- Baer, G.M. History of Rabies and Global Aspects; CRC Press: Boca Raton, FL, USA, 2017; pp. 1–24. [Google Scholar] [CrossRef]
- Sperk, M.; Van Domselaar, R.; Rodriguez, J.E.; Mikaeloff, F.; Sá Vinhas, B.; Saccon, E.; Sönnerborg, A.; Singh, K.; Gupta, S.; Végvári, Á.; et al. Utility of Proteomics in Emerging and Re-Emerging Infectious Diseases Caused by RNA Viruses. J. Proteome Res. 2020, 19, 4259–4274. [Google Scholar] [CrossRef] [PubMed]
- Çelik, İ.; Saatçi, E.; Eyüboğlu, F.Ö. Emerging and Reemerging Respiratory Viral Infections up to COVID-19. Turk. J. Med. Sci. 2020, 50, 557–562. [Google Scholar] [CrossRef]
- Curry, S. Structural Biology: A Century-Long Journey into an Unseen World. Interdiscip. Sci. Rev. 2015, 40, 308–328. [Google Scholar] [CrossRef]
- Brooks-Bartlett, J.C.; Garman, E.F. The Nobel Science: One Hundred Years of Crystallography. Interdiscip. Sci. Rev. 2015, 40, 244–264. [Google Scholar] [CrossRef]
- Thomas, J.M. Centenary: The Birth of X-Ray Crystallography. Nature 2012, 491, 186–187. [Google Scholar] [CrossRef] [PubMed]
- Shi, Y. A Glimpse of Structural Biology through X-Ray Crystallography. Cell 2014, 159, 995–1014. [Google Scholar] [CrossRef] [PubMed]
- De Clercq, E.; Li, G. Approved Antiviral Drugs over the Past 50 Years. Clin. Microbiol. Rev. 2016, 29, 695–747. [Google Scholar] [CrossRef]
- Zheng, H.; Handing, K.B.; Zimmerman, M.D.; Shabalin, I.G.; Almo, S.C.; Minor, W. X-Ray Crystallography over the Past Decade for Novel Drug Discovery—Where Are We Heading Next? Expert Opin. Drug Discov. 2015, 10, 975–989. [Google Scholar] [CrossRef]
- Stanley, W.M. Isolation of a crystalline protein possessing the properties of tobacco-mosaic virus. Science 1935, 81, 644–645. [Google Scholar] [CrossRef]
- Norrby, E. Nobel Prizes and the Emerging Virus Concept. Arch. Virol. 2008, 153, 1109–1123. [Google Scholar] [CrossRef]
- Bernal, J.D.; Fankuchen, I. X-Ray and crystallographic studies of plant virus preparations: I. introduction and preparation of specimens II. modes of aggregation of the virus particles. J. Gen. Physiol. 1941, 25, 111–146. [Google Scholar] [CrossRef] [PubMed]
- Harrison, S.C.; Olson, A.J.; Schutt, C.E.; Winkler, F.K.; Bricogne, G. Tomato Bushy Stunt Virus at 2.9 A Resolution. Nature 1978, 276, 368–373. [Google Scholar] [CrossRef]
- Bloomer, A.C.; Champness, J.N.; Bricogne, G.; Staden, R.; Klug, A. Protein Disk of Tobacco Mosaic Virus at 2.8 A Resolution Showing the Interactions within and between Subunits. Nature 1978, 276, 362–368. [Google Scholar] [CrossRef]
- Richmond, T.J.; Finch, J.T.; Rushton, B.; Rhodes, D.; Klug, A. Structure of the Nucleosome Core Particle at 7 A Resolution. Nature 1984, 311, 532–537. [Google Scholar] [CrossRef] [PubMed]
- Schirò, A.; Carlon, A.; Parigi, G.; Murshudov, G.; Calderone, V.; Ravera, E.; Luchinat, C. On the Complementarity of X-Ray and NMR Data. J. Struct. Biol. X 2020, 4, 100019. [Google Scholar] [CrossRef]
- Holcomb, J.; Spellmon, N.; Zhang, Y.; Doughan, M.; Li, C.; Yang, Z. Protein Crystallization: Eluding the Bottleneck of X-Ray Crystallography. AIMS Biophys. 2017, 4, 557–575. [Google Scholar] [CrossRef]
- Vincenzi, M.; Leone, M. The Fight against Human Viruses: How NMR Can Help? Curr. Med. Chem. 2021, 28, 4380–4453. [Google Scholar] [CrossRef] [PubMed]
- Yu, H. Extending the Size Limit of Protein Nuclear Magnetic Resonance. Proc. Natl. Acad. Sci. USA 1999, 96, 332–334. [Google Scholar] [CrossRef]
- LaPlante, S.R.; Coric, P.; Bouaziz, S.; França, T.C.C. NMR Spectroscopy Can Help Accelerate Antiviral Drug Discovery Programs. Microbes Infect. 2024, 26, 105297. [Google Scholar] [CrossRef]
- Kruger, D.H.; Schneck, P.; Gelderblom, H.R. Helmut Ruska and the Visualisation of Viruses. Lancet 2000, 355, 1713–1717. [Google Scholar] [CrossRef]
- Nagler, F.P.; Rake, G. The Use of the Electron Microscope in Diagnosis of Variola, Vaccinia, and Varicella. J. Bacteriol. 1948, 55, 45–51. [Google Scholar] [CrossRef]
- Brenner, S.; Horne, R.W. A Negative Staining Method for High Resolution Electron Microscopy of Viruses. Biochim. Biophys. Acta 1959, 34, 103–110. [Google Scholar] [CrossRef] [PubMed]
- Tyrrell, D.A.J.; Almeida, J.D. Direct Electron-Microscopy of Organ Cultures for the Detection and Characterization of Viruses. Arch. Gesamte Virusforsch. 1967, 22, 417–425. [Google Scholar] [CrossRef]
- Adrian, M.; Dubochet, J.; Lepault, J.; McDowall, A.W. Cryo-Electron Microscopy of Viruses. Nature 1984, 308, 32–36. [Google Scholar] [CrossRef] [PubMed]
- Schoehn, G.; Chenavier, F.; Crépin, T. Advances in Structural Virology via Cryo-EM in 2022. Viruses 2023, 15, 1315. [Google Scholar] [CrossRef]
- Dutta, M.; Acharya, P. Cryo-Electron Microscopy in the Study of Virus Entry and Infection. Front. Mol. Biosci. 2024, 11, 1429180. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Li, S.; Zhang, K. Cryo-EM: A Window into the Dynamic World of RNA Molecules. Curr. Opin. Struct. Biol. 2024, 88, 102916. [Google Scholar] [CrossRef]
- Wu, X.; Rapoport, T.A. Cryo-EM Structure Determination of Small Proteins by Nanobody-Binding Scaffolds (Legobodies). Proc. Natl. Acad. Sci. USA 2021, 118, e2115001118. [Google Scholar] [CrossRef]
- Renaud, J.P.; Chari, A.; Ciferri, C.; Liu, W.T.; Rémigy, H.W.; Stark, H.; Wiesmann, C. Cryo-EM in Drug Discovery: Achievements, Limitations and Prospects. Nat. Rev. Drug Discov. 2018, 17, 471–492. [Google Scholar] [CrossRef]
- Boldon, L.; Laliberte, F.; Liu, L. Review of the Fundamental Theories behind Small Angle X-Ray Scattering, Molecular Dynamics Simulations, and Relevant Integrated Application. Nano Rev. 2015, 6, 25661. [Google Scholar] [CrossRef]
- Handa, T.; Kundu, D.; Dubey, V.K. Perspectives on Evolutionary and Functional Importance of Intrinsically Disordered Proteins. Int. J. Biol. Macromol. 2023, 224, 243–255. [Google Scholar] [CrossRef] [PubMed]
- Barradas-Bautista, D.; Rosell, M.; Pallara, C.; Fernández-Recio, J. Structural Prediction of Protein–Protein Interactions by Docking: Application to Biomedical Problems. Adv. Protein Chem. Struct. Biol. 2018, 110, 203–249. [Google Scholar] [CrossRef] [PubMed]
- Zhu, P.; Winkler, H.; Chertova, E.; Taylor, K.A.; Roux, K.H. Cryoelectron Tomography of HIV-1 Envelope Spikes: Further Evidence for Tripod-like Legs. PLoS Pathog. 2008, 4, e1000203. [Google Scholar] [CrossRef] [PubMed]
- Baumeister, W. Cryo-Electron Tomography: The Power of Seeing the Whole Picture. Biochem. Biophys. Res. Commun. 2022, 633, 26–28. [Google Scholar] [CrossRef]
- Meents, A.; Wiedorn, M.O. Virus Structures by X-Ray Free-Electron Lasers. Annu. Rev. Virol. 2019, 6, 161–176. [Google Scholar] [CrossRef]
- Wang, J. Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) through Computational Drug Repurposing Study. J. Chem. Inf. Model 2020, 60, 3277–3286. [Google Scholar] [CrossRef]
- Singh, A.; Dhaka, P.; Kumar, P.; Tomar, S.; Singla, J. Bioinformatics Databases and Tools Available for the Development of Antiviral Drugs. In Advances in Antiviral Research; Springer: Singapore, 2024; pp. 41–71. [Google Scholar] [CrossRef]
- Abramson, J.; Adler, J.; Dunger, J.; Evans, R.; Green, T.; Pritzel, A.; Ronneberger, O.; Willmore, L.; Ballard, A.J.; Bambrick, J.; et al. Accurate Structure Prediction of Biomolecular Interactions with AlphaFold 3. Nature 2024, 630, 493–500. [Google Scholar] [CrossRef]
- O’Leary, K. AlphaFold Gets an Upgrade (and a Nobel). Nat. Med. 2024, 30, 3393. [Google Scholar] [CrossRef] [PubMed]
- Fenner, F.; Bachmann, P.A.; Gibbs, E.P.J.; Murphy, F.A.; Studdert, M.J.; White, D.O. Structure and Composition of Viruses. In Veterinary Virology; Elsevier: Amsterdam, The Netherlands, 1987; pp. 3–19. [Google Scholar]
- Zheng, B.; Duan, M.; Huang, Y.; Wang, S.; Qiu, J.; Lu, Z.; Liu, L.; Tang, G.; Cheng, L.; Zheng, P. Discovery of a Heparan Sulfate Binding Domain in Monkeypox Virus H3 as an Anti-Poxviral Drug Target Combining AI and MD Simulations. Elife 2024, 13, RP100545. [Google Scholar] [CrossRef]
- Delogu, I.; Pastorino, B.; Baronti, C.; Nougairède, A.; Bonnet, E.; de Lamballerie, X. In Vitro Antiviral Activity of Arbidol against Chikungunya Virus and Characteristics of a Selected Resistant Mutant. Antivir. Res. 2011, 90, 99–107. [Google Scholar] [CrossRef]
- Barrow, E.; Nicola, A.V.; Liu, J. Multiscale Perspectives of Virus Entry via Endocytosis. Virol. J. 2013, 10, 177. [Google Scholar] [CrossRef] [PubMed]
- Kim, A.S.; Diamond, M.S. A Molecular Understanding of Alphavirus Entry and Antibody Protection. Nat. Rev. Microbiol. 2022, 21, 396–407. [Google Scholar] [CrossRef]
- Melton, J.V.; Ewart, G.D.; Weir, R.C.; Board, P.G.; Lee, E.; Gage, P.W. Alphavirus 6K Proteins Form Ion Channels. J. Biol. Chem. 2002, 277, 46923–46931. [Google Scholar] [CrossRef] [PubMed]
- Button, J.M.; Mukhopadhyay, S. Capsid-E2 Interactions Rescue Core Assembly in Viruses That Cannot Form Cytoplasmic Nucleocapsid Cores. J. Virol. 2021, 95, e01062-21. [Google Scholar] [CrossRef]
- Liu, D.X.; Liang, J.Q.; Fung, T.S. Human Coronavirus-229E, -OC43, -NL63, and -HKU1 (Coronaviridae). In Encyclopedia of Virology: Volume 1–5, 4th ed.; Academic Press: Amsterdam, The Netherlands, 2021; Volume 1–5, pp. 428–440. [Google Scholar] [CrossRef]
- Schlicksup, C.J.; Zlotnick, A. Viral Structural Proteins as Targets for Antivirals. Curr. Opin. Virol. 2020, 45, 43–50. [Google Scholar] [CrossRef] [PubMed]
- Chen, N.; Zhang, B.; Deng, L.; Liang, B.; Ping, J. Virus-Host Interaction Networks as New Antiviral Drug Targets for IAV and SARS-CoV-2. Emerg. Microbes Infect. 2022, 11, 1371–1389. [Google Scholar] [CrossRef]
- Burrell, C.J.; Howard, C.R.; Murphy, F.A. Virion Structure and Composition. Fenner White’s Med. Virol. 2017, 27–37. [Google Scholar] [CrossRef]
- Kaur, R.; Neetu; Mudgal, R.; Jose, J.; Kumar, P.; Tomar, S. Glycan-Dependent Chikungunya Viral Infection Divulged by Antiviral Activity of NAG Specific Chi-like Lectin. Virology 2019, 526, 91–98. [Google Scholar] [CrossRef]
- Kosik, I.; Yewdell, J.W. Influenza Hemagglutinin and Neuraminidase: Yin–Yang Proteins Coevolving to Thwart Immunity. Viruses 2019, 11, 346. [Google Scholar] [CrossRef]
- Checkley, M.A.; Luttge, B.G.; Freed, E.O. HIV-1 Envelope Glycoprotein Biosynthesis, Trafficking, and Incorporation. J. Mol. Biol. 2011, 410, 582–608. [Google Scholar] [CrossRef]
- Wrobel, A.G. Mechanism and Evolution of Human ACE2 Binding by SARS-CoV-2 Spike. Curr. Opin. Struct. Biol. 2023, 81, 102619. [Google Scholar] [CrossRef] [PubMed]
- Epand, R.M. Fusion Peptides and the Mechanism of Viral Fusion. Biochim. Biophys. Acta (BBA) Biomembr. 2003, 1614, 116–121. [Google Scholar] [CrossRef]
- Zhai, X.; Yuan, Y.; He, W.T.; Wu, Y.; Shi, Y.; Su, S.; Du, Q.; Mao, Y. Evolving Roles of Glycosylation in the Tug-of-War between Virus and Host. Natl. Sci. Rev. 2024, 11, nwae086. [Google Scholar] [CrossRef]
- Matsuyama, S.; Taguchi, F. Two-Step Conformational Changes in a Coronavirus Envelope Glycoprotein Mediated by Receptor Binding and Proteolysis. J. Virol. 2009, 83, 11133. [Google Scholar] [CrossRef] [PubMed]
- Marzinek, J.K.; Raghuvamsi Palur, V.; Salem, G.; Chen, F.-C.; Wu, S.-R.; Bond, P.J.; Chao, D.-Y. Uncovering the Conformational Dynamics of Dengue Virus and Its Virus-like Particles as Novel Vaccine Candidates. Biophys. J. 2023, 122, 508a–509a. [Google Scholar] [CrossRef]
- Chen, F.; Nagy, K.; Chavez, D.; Willis, S.; McBride, R.; Giang, E.; Honda, A.; Bukh, J.; Ordoukhanian, P.; Zhu, J.; et al. Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B-Cell-Based Vaccine Development. Gastroenterology 2020, 158, 1058–1071.e6. [Google Scholar] [CrossRef]
- Katze, M.G.; He, Y.; Gale, M. Viruses and Interferon: A Fight for Supremacy. Nat. Rev. Immunol. 2002, 2, 675–687. [Google Scholar] [CrossRef]
- Zhang, S.; Xue, X.; Qiao, S.; Jia, L.; Wen, X.; Wang, Y.; Wang, C.; Li, H.; Cui, J. Umifenovir Epigenetically Targets the IL-10 Pathway in Therapy against Coxsackievirus B4 Infection. Microbiol. Spectr. 2023, 11, e04248-22. [Google Scholar] [CrossRef]
- Sargsyan, K.; Mazmanian, K.; Lim, C. A Strategy for Evaluating Potential Antiviral Resistance to Small Molecule Drugs and Application to SARS-CoV-2. Sci. Rep. 2023, 13, 502. [Google Scholar] [CrossRef]
- McCallum, M.; Czudnochowski, N.; Rosen, L.E.; Zepeda, S.K.; Bowen, J.E.; Walls, A.C.; Hauser, K.; Joshi, A.; Stewart, C.; Dillen, J.R.; et al. Structural Basis of SARS-CoV-2 Omicron Immune Evasion and Receptor Engagement. Science 2022, 375, 894–898. [Google Scholar] [CrossRef]
- Tang, H.; Ke, Y.; Liao, Y.; Bian, Y.; Yuan, Y.; Wang, Z.; Yang, L.; Ma, H.; Sun, T.; Zhang, B.; et al. Mutational Escape Prevention by Combination of Four Neutralizing Antibodies That Target RBD Conserved Regions and Stem Helix. Virol. Sin. 2022, 37, 860–873. [Google Scholar] [CrossRef] [PubMed]
- Shih, H.I.; Wang, Y.C.; Wang, Y.P.; Chi, C.Y.; Chien, Y.W. Risk of Severe Dengue during Secondary Infection: A Population-Based Cohort Study in Taiwan. J. Microbiol. Immunol. Infect. 2024, 57, 730–738. [Google Scholar] [CrossRef]
- Wells, T.J.; Esposito, T.; Henderson, I.R.; Labzin, L.I. Mechanisms of Antibody-Dependent Enhancement of Infectious Disease. Nat. Rev. Immunol. 2024, 25, 6–21. [Google Scholar] [CrossRef]
- Sarker, A.; Dhama, N.; Gupta, R.D. Dengue Virus Neutralizing Antibody: A Review of Targets, Cross-Reactivity, and Antibody-Dependent Enhancement. Front. Immunol. 2023, 14, 1200195. [Google Scholar] [CrossRef]
- Malik, S.; Ahsan, O.; Mumtaz, H.; Tahir Khan, M.; Sah, R.; Waheed, Y. Tracing down the Updates on Dengue Virus—Molecular Biology, Antivirals, and Vaccine Strategies. Vaccines 2023, 11, 1328. [Google Scholar] [CrossRef] [PubMed]
- Dengvaxia|European Medicines Agency (EMA). Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/dengvaxia (accessed on 10 January 2025).
- Ragonnet-Cronin, M.; Nutalai, R.; Huo, J.; Dijokaite-Guraliuc, A.; Das, R.; Tuekprakhon, A.; Supasa, P.; Liu, C.; Selvaraj, M.; Groves, N.; et al. Generation of SARS-CoV-2 Escape Mutations by Monoclonal Antibody Therapy. Nat. Commun. 2023, 14, 3334. [Google Scholar] [CrossRef]
- Choudhary, S.; Malik, Y.S.; Tomar, S. Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in Silico Structure-Based Virtual Screening Approach. Front. Immunol. 2020, 11, 1664. [Google Scholar] [CrossRef] [PubMed]
- Hayden, F.G.; Osterhaus, A.D.M.E.; Treanor, J.J.; Fleming, D.M.; Aoki, F.Y.; Nicholson, K.G.; Bohnen, A.M.; Hirst, H.M.; Keene, O.; Wightman, K. Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections. N. Engl. J. Med. 1997, 337, 874–880. [Google Scholar] [CrossRef]
- Collins, P.J.; Haire, L.F.; Lin, Y.P.; Liu, J.; Russell, R.J.; Walker, P.A.; Skehel, J.J.; Martin, S.R.; Hay, A.J.; Gamblin, S.J. Crystal Structures of Oseltamivir-Resistant Influenza Virus Neuraminidase Mutants. Nature 2008, 453, 1258–1261. [Google Scholar] [CrossRef]
- Vavricka, C.J.; Li, Q.; Wu, Y.; Qi, J.; Wang, M.; Liu, Y.; Gao, F.; Liu, J.; Feng, E.; He, J.; et al. Structural and Functional Analysis of Laninamivir and Its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition. PLoS Pathog. 2011, 7, e1002249. [Google Scholar] [CrossRef]
- Pattnaik, G.P.; Chakraborty, H. Entry Inhibitors: Efficient Means to Block Viral Infection. J. Membr. Biol. 2020, 253, 425–444. [Google Scholar] [CrossRef]
- Beugeling, M.; De Zee, J.; Woerdenbag, H.J.; Frijlink, H.W.; Wilschut, J.C.; Hinrichs, W.L.J. Respiratory Syncytial Virus Subunit Vaccines Based on the Viral Envelope Glycoproteins Intended for Pregnant Women and the Elderly. Expert Rev. Vaccines 2019, 18, 935–950. [Google Scholar] [CrossRef] [PubMed]
- Singh, V.A.; Nehul, S.; Kumar, C.S.; Banerjee, M.; Kumar, P.; Sharma, G.; Tomar, S. Chimeric Chikungunya Virus-like Particles with Surface Exposed SARS-CoV-2 RBD Elicits Potent Immunogenic Responses in Mice. bioRxiv 2023. bioRxiv:2023.01.29.526074. [Google Scholar] [CrossRef]
- Singh, V.A.; Kumar, C.S.; Khare, B.; Kuhn, R.J.; Banerjee, M.; Tomar, S. Surface Decorated Reporter-Tagged Chikungunya Virus-like Particles for Clinical Diagnostics and Identification of Virus Entry Inhibitors. Virology 2023, 578, 92–102. [Google Scholar] [CrossRef]
- Nieva, J.L.; Madan, V.; Carrasco, L. Viroporins: Structure and Biological Functions. Nat. Rev. Microbiol. 2012, 10, 563–574. [Google Scholar] [CrossRef] [PubMed]
- Xia, X.; Cheng, A.; Wang, M.; Ou, X.; Sun, D.; Mao, S.; Huang, J.; Yang, Q.; Wu, Y.; Chen, S.; et al. Functions of Viroporins in the Viral Life Cycle and Their Regulation of Host Cell Responses. Front. Immunol. 2022, 13, 890549. [Google Scholar] [CrossRef] [PubMed]
- Devantier, K.; Kjær, V.M.S.; Griffin, S.; Kragelund, B.B.; Rosenkilde, M.M. Advancing the Field of Viroporins—Structure, Function and Pharmacology: IUPHAR Review 39. Br. J. Pharmacol. 2024, 181, 4450–4490. [Google Scholar] [CrossRef]
- Pinto, L.H.; Holsinger, L.J.; Lamb, R.A. Influenza Virus M2 Protein Has Ion Channel Activity. Cell 1992, 69, 517–528. [Google Scholar] [CrossRef]
- Surya, W.; Samsó, M.; Torres, J. Structural and Functional Aspects of Viroporins in Human Respiratory Viruses: Respiratory Syncytial Virus and Coronaviruses. In Respiratory Disease and Infection-A New Insight; TechOpen: London, UK, 2013. [Google Scholar] [CrossRef]
- Das, K. Antivirals Targeting Influenza a Virus. J. Med. Chem. 2012, 55, 6263–6277. [Google Scholar] [CrossRef]
- Thomaston, J.L.; Polizzi, N.F.; Konstantinidi, A.; Wang, J.; Kolocouris, A.; Degrado, W.F. Inhibitors of the M2 Proton Channel Engage and Disrupt Transmembrane Networks of Hydrogen-Bonded Waters. J. Am. Chem. Soc. 2018, 140, 15219–15226. [Google Scholar] [CrossRef]
- Nieto-Torres, J.L.; Verdiá-Báguena, C.; Castaño-Rodriguez, C.; Aguilella, V.M.; Enjuanes, L. Relevance of Viroporin Ion Channel Activity on Viral Replication and Pathogenesis. Viruses 2015, 7, 3552–3573. [Google Scholar] [CrossRef] [PubMed]
- Dey, D.; Siddiqui, S.I.; Mamidi, P.; Ghosh, S.; Kumar, C.S.; Chattopadhyay, S.; Ghosh, S.; Banerjee, M. The Effect of Amantadine on an Ion Channel Protein from Chikungunya Virus. PLoS Negl. Trop. Dis. 2019, 13, e0007548. [Google Scholar] [CrossRef] [PubMed]
- Lamb, R.A. Influenza. Encycl. Virol. 2008, 1–5, 95–104. [Google Scholar] [CrossRef]
- Scott, C.; Griffin, S. Viroporins: Structure, Function and Potential as Antiviral Targets. J. Gen. Virol. 2015, 96, 2000–2027. [Google Scholar] [CrossRef] [PubMed]
- Fatma, B.; Kumar, R.; Singh, V.A.; Nehul, S.; Sharma, R.; Kesari, P.; Kuhn, R.J.; Tomar, S. Alphavirus Capsid Protease Inhibitors as Potential Antiviral Agents for Chikungunya Infection. Antivir. Res. 2020, 179, 104808. [Google Scholar] [CrossRef]
- Chakravarty, A.; Rao, A.L. The Interplay between Capsid Dynamics and Pathogenesis in Tripartite Bromoviruses. Curr. Opin. Virol. 2021, 47, 45–51. [Google Scholar] [CrossRef]
- Ghaemi, Z.; Gruebele, M.; Tajkhorshid, E. Molecular Mechanism of Capsid Disassembly in Hepatitis B Virus. Proc. Natl. Acad. Sci. USA 2021, 118, e2102530118. [Google Scholar] [CrossRef]
- Mohajerani, F.; Tyukodi, B.; Schlicksup, C.J.; Hadden-Perilla, J.A.; Zlotnick, A.; Hagan, M.F. Multiscale Modeling of Hepatitis B Virus Capsid Assembly and Its Dimorphism. ACS Nano 2022, 16, 13845–13859. [Google Scholar] [CrossRef]
- Koehl, P.; Akopyan, A.; Edelsbrunner, H. Computing the Volume, Surface Area, Mean, and Gaussian Curvatures of Molecules and Their Derivatives. J. Chem. Inf. Model 2023, 63, 973–985. [Google Scholar] [CrossRef]
- Aggarwal, M.; Kaur, R.; Saha, A.; Mudgal, R.; Yadav, R.; Dash, P.K.; Parida, M.; Kumar, P.; Tomar, S. Evaluation of Antiviral Activity of Piperazine against Chikungunya Virus Targeting Hydrophobic Pocket of Alphavirus Capsid Protein. Antivir. Res. 2017, 146, 102–111. [Google Scholar] [CrossRef]
- Thenin-Houssier, S.; T Valente, S. HIV-1 Capsid Inhibitors as Antiretroviral Agents. Curr. HIV Res. 2016, 14, 270–282. [Google Scholar] [CrossRef] [PubMed]
- Segal-Maurer, S.; DeJesus, E.; Stellbrink, H.-J.; Castagna, A.; Richmond, G.J.; Sinclair, G.I.; Siripassorn, K.; Ruane, P.J.; Berhe, M.; Wang, H.; et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N. Engl. J. Med. 2022, 386, 1793–1803. [Google Scholar] [CrossRef]
- Klumpp, K.; Crépin, T. Capsid Proteins of Enveloped Viruses as Antiviral Drug Targets. Curr. Opin. Virol. 2014, 5, 63–71. [Google Scholar] [CrossRef]
- Zhang, X.; Zhang, Y.; Jia, R.; Wang, M.; Yin, Z.; Cheng, A. Structure and Function of Capsid Protein in Flavivirus Infection and Its Applications in the Development of Vaccines and Therapeutics. Vet. Res. 2021, 52, 1–14. [Google Scholar] [CrossRef]
- Zhang, X.; Jia, R.; Zhou, J.; Wang, M.; Yin, Z.; Cheng, A. Capsid-Targeted Viral Inactivation: A Novel Tactic for Inhibiting Replication in Viral Infections. Viruses 2016, 8, 258. [Google Scholar] [CrossRef] [PubMed]
- Dhaka, P.; Mahto, J.K.; Singh, A.; Kumar, P.; Tomar, S. Structural Insights into the RNA Binding Inhibitors of the C-Terminal Domain of the SARS-CoV-2 Nucleocapsid. bioRxiv 2024. [Google Scholar] [CrossRef]
- Dhaka, P.; Singh, A.; Choudhary, S.; Peddinti, R.K.; Kumar, P.; Sharma, G.K.; Tomar, S. Mechanistic and Thermodynamic Characterization of Antiviral Inhibitors Targeting Nucleocapsid N-Terminal Domain of SARS-CoV-2. Arch. Biochem. Biophys. 2023, 750, 109820. [Google Scholar] [CrossRef] [PubMed]
- Stanley, W.M. The Isolation and Properties of Crystalline Tobacco Mosaic Virus. Nobel Lect. 1946, 12, 1942–1962. [Google Scholar]
- Namba, K.; Pattanayek, R.; Stubbs, G. Visualization of Protein-Nucleic Acid Interactions in a Virus: Refined Structure of Intact Tobacco Mosaic Virus at 2.9 Å Resolution by X-Ray Fiber Diffraction. J. Mol. Biol. 1989, 208, 307–325. [Google Scholar] [CrossRef]
- Aggarwal, M.; Tapas, S.; Preeti; Siwach, A.; Kumar, P.; Kuhn, R.J.; Tomar, S. Crystal Structure of Aura Virus Capsid Protease and Its Complex with Dioxane: New Insights into Capsid-Glycoprotein Molecular Contacts. PLoS ONE 2012, 7, e51288. [Google Scholar] [CrossRef] [PubMed]
- Aggarwal, M.; Dhindwal, S.; Kumar, P.; Kuhn, R.J.; Tomar, S. Trans -Protease Activity and Structural Insights into the Active Form of the Alphavirus Capsid Protease. J. Virol. 2014, 88, 12242–12253. [Google Scholar] [CrossRef] [PubMed]
- Kanodia, S.; Da Silva, D.M.; Kast, W.M. Recent Advances in Strategies for Immunotherapy of Human Papillomavirus-Induced Lesions. Int. J. Cancer 2008, 122, 247–259. [Google Scholar] [CrossRef]
- Demmler-Harrison, G.J. Antiviral Agents. In Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 6th ed.; Saunders/Elsevier: Philadelphia, PA, USA, 2009; pp. 3245–3271. [Google Scholar] [CrossRef]
- Wlodawer, A.; Vondrasek, J. Inhibitors of HIV-1 Protease: A Major Success of Structure-Assisted Drug Design. Annu. Rev. Biophys. Biomol. Struct. 1998, 27, 249–284. [Google Scholar] [CrossRef] [PubMed]
- FDA-Approved HIV Medicines|NIH. Available online: https://hivinfo.nih.gov/understanding-hiv/fact-sheets/fda-approved-hiv-medicines (accessed on 27 December 2024).
- Weber, I.T.; Miller, M.; Jaskólski, M.; Leis, J.; Skalka, A.M.; Wlodawer, A. Molecular Modeling of the HIV-1 Protease and Its Substrate Binding Site. Science 1989, 243, 928–931. [Google Scholar] [CrossRef] [PubMed]
- Lapatto, R.; Blundell, T.; Hemmings, A.; Overington, J.; Wilderspin, A.; Wood, S.; Merson, J.R.; Whittle, P.J.; Danley, D.E.; Geoghegan, K.F.; et al. X-Ray Analysis of HIV-1 Proteinase at 2.7 Å Resolution Confirms Structural Homology among Retroviral Enzymes. Nature 1989, 342, 299–302. [Google Scholar] [CrossRef]
- Roberts, N.A.; Martin, J.A.; Kinchington, D.; Broadhurst, A.V.; Craig, J.C.; Duncan, I.B.; Galpin, S.A.; Handa, B.K.; Kay, J.; Kröhn, A.; et al. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science (1979) 1990, 248, 358–361. [Google Scholar] [CrossRef]
- Craig, J.C.; Duncan, I.B.; Hockley, D.; Grief, C.; Roberts, N.A.; Mills, J.S. Antiviral Properties of Ro 31-8959, an Inhibitor of Human Immunodeficiency Virus (HIV) Proteinase. Antivir. Res. 1991, 16, 295–305. [Google Scholar] [CrossRef]
- Kempf, D.J.; Marsh, K.C.; Denissen, J.F.; McDonald, E.; Vasavanonda, S.; Flentge, C.A.; Green, B.E.; Fino, L.; Park, C.H.; Kong, X.P.; et al. ABT-538 Is a Potent Inhibitor of Human Immunodeficiency Virus Protease and Has High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. USA 1995, 92, 2484–2488. [Google Scholar] [CrossRef]
- Erickson, J.W. Design and Structure of Symmetry-Based Inhibitors of HIV-1 Protease. Perspect. Drug Discov. Des. 1993, 1, 109–128. [Google Scholar] [CrossRef]
- Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; Vacca, J.P.; Guare, J.P.; Anderson, P.S.; Huff, J.R.; Darke, P.L.; Zugay, J.A.; Emini, E.A.; et al. L-735,524: The Design of a Potent and Orally Bioavailable HIV Protease Inhibitor. J. Med. Chem. 1994, 37, 3443–3451. [Google Scholar] [CrossRef]
- Vacca, J.P.; Dorsey, B.D.; Schleif, W.A.; Levin, R.B.; Mcdaniel, S.L.; Darke, P.L.; Zugay, J.; Quintero, J.C.; Blahy, O.M.; Roth, E.; et al. L-735,524: An Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. USA 1994, 91, 4096–4100. [Google Scholar] [CrossRef] [PubMed]
- Wlodawer, A. Rational Approach to AIDS Drug Design through Structural Biology. Annu. Rev. Med. 2002, 53, 595–614. [Google Scholar] [CrossRef] [PubMed]
- Varney, M.D.; Appelt, K.; Kalish, V.; Reddy, M.R.; Tatlock, J.; Palmer, C.L.; Romines, W.H.; Wu, B.W.; Musick, L. Crystal-Structure-Based Design and Synthesis of Novel C-Terminal Inhibitors of HIV Protease. J. Med. Chem. 1994, 37, 2274–2284. [Google Scholar] [CrossRef]
- Kaldor, S.W.; Kalish, V.J.; Davies, J.F.; Shetty, B.V.; Fritz, J.E.; Appelt, K.; Burgess, J.A.; Campanale, K.M.; Chirgadze, N.Y.; Clawson, D.K.; et al. Viracept (Nelfinavir Mesylate, AG1343): A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease. J. Med. Chem. 1997, 40, 3979–3985. [Google Scholar] [CrossRef]
- Weber, I.T.; Waltman, M.J.; Mustyakimov, M.; Blakeley, M.P.; Keen, D.A.; Ghosh, A.K.; Langan, P.; Kovalevsky, A.Y. Joint X-Ray/Neutron Crystallographic Study of HIV-1 Protease with Clinical Inhibitor Amprenavir: Insights for Drug Design. J. Med. Chem. 2013, 56, 5631–5635. [Google Scholar] [CrossRef] [PubMed]
- Chemburkar, S.R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.; Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; et al. Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development. Org. Process. Res. Dev. 2000, 4, 413–417. [Google Scholar] [CrossRef]
- McCauley, J.A.; Rudd, M.T. Hepatitis C Virus NS3/4a Protease Inhibitors. Curr. Opin. Pharmacol. 2016, 30, 84–92. [Google Scholar] [CrossRef]
- Love, R.A.; Parge, H.E.; Wickersham, J.A.; Hostomsky, Z.; Habuka, N.; Moomaw, E.W.; Adachi, T.; Hostomska, Z. The Crystal Structure of Hepatitis C Virus NS3 Proteinase Reveals a Trypsin-like Fold and a Structural Zinc Binding Site. Cell 1996, 87, 331–342. [Google Scholar] [CrossRef]
- Kim, J.L.; Morgenstern, K.A.; Lin, C.; Fox, T.; Dwyer, M.D.; Landro, J.A.; Chambers, S.P.; Markland, W.; Lepre, C.A.; O’Malley, E.T.; et al. Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4A Cofactor Peptide. Cell 1996, 87, 343–355. [Google Scholar] [CrossRef]
- Barbato, G.; Cicero, D.O.; Nardi, M.C.; Steinkühler, C.; Cortese, R.; De Francesco, R.; Bazzo, R. The Solution Structure of the N-Terminal Proteinase Domain of the Hepatitis C Virus (HCV) NS3 Protein Provides New Insights into Its Activation and Catalytic Mechanism. J. Mol. Biol. 1999, 289, 371–384. [Google Scholar] [CrossRef]
- Llinàs-Brunet, M.; Bailey, M.; Fazal, G.; Goulet, S.; Halmos, T.; Laplante, S.; Maurice, R.; Poirier, M.; Poupart, M.A.; Thibeault, D.; et al. Peptide-Based Inhibitors of the Hepatitis C Virus Serine Protease. Bioorg. Med. Chem. Lett. 1998, 8, 1713–1718. [Google Scholar] [CrossRef]
- Saalau-Bethell, S.M.; Woodhead, A.J.; Chessari, G.; Carr, M.G.; Coyle, J.; Graham, B.; Hiscock, S.D.; Murray, C.W.; Pathuri, P.; Rich, S.J.; et al. Discovery of an Allosteric Mechanism for the Regulation of HcV Ns3 Protein Function. Nat. Chem. Biol. 2012, 8, 920–925. [Google Scholar] [CrossRef]
- Choudhary, S.; Nehul, S.; Singh, A.; Panda, P.K.; Kumar, P.; Sharma, G.K.; Tomar, S. Unraveling Antiviral Efficacy of Multifunctional Immunomodulatory Triterpenoids against SARS-COV-2 Targeting Main Protease and Papain-like Protease. IUBMB Life 2024, 76, 228–241. [Google Scholar] [CrossRef]
- Choudhary, S.; Nehul, S.; Nagaraj, S.K.; Narayan, R.; Verma, S.; Sharma, S.; Kumari, A.; Rani, R.; Saha, A.; Sircar, D.; et al. Activity Profiling of Deubiquitinating Inhibitors-Bound to SARS-CoV-2 Papain like Protease with Antiviral Efficacy in Murine Infection Model. bioRxiv 2022. [Google Scholar] [CrossRef]
- Owen, D.R.; Allerton, C.M.N.; Anderson, A.S.; Aschenbrenner, L.; Avery, M.; Berritt, S.; Boras, B.; Cardin, R.D.; Carlo, A.; Coffman, K.J.; et al. An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19. Science 2021, 374, 1586–1593. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Lin, D.; Sun, X.; Curth, U.; Drosten, C.; Sauerhering, L.; Becker, S.; Rox, K.; Hilgenfeld, R. Crystal Structure of SARS-CoV-2 Main Protease Provides a Basis for Design of Improved a-Ketoamide Inhibitors. Science 2020, 368, 409–412. [Google Scholar] [CrossRef] [PubMed]
- FDA. Approves First Oral Antiviral for Treatment of COVID-19 in Adults|FDA. Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-antiviral-treatment-covid-19-adults (accessed on 30 December 2024).
- Pagliano, P.; Spera, A.; Sellitto, C.; Scarpati, G.; Folliero, V.; Piazza, O.; Franci, G.; Conti, V.; Ascione, T. Preclinical Discovery and Development of Nirmatrelvir/Ritonavir Combinational Therapy for the Treatment of COVID-19 and the Lessons Learned from SARS-COV-2 Variants. Expert Opin. Drug Discov. 2023, 18, 1301–1311. [Google Scholar] [CrossRef]
- Unoh, Y.; Uehara, S.; Nakahara, K.; Nobori, H.; Yamatsu, Y.; Yamamoto, S.; Maruyama, Y.; Taoda, Y.; Kasamatsu, K.; Suto, T.; et al. Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19. J. Med. Chem. 2022, 65, 6499–6512. [Google Scholar] [CrossRef]
- Narwal, M.; Armache, J.P.; Edwards, T.J.; Murakami, K.S. SARS-CoV-2 Polyprotein Substrate Regulates the Stepwise Mpro Cleavage Reaction. J. Biol. Chem. 2023, 299, 104697. [Google Scholar] [CrossRef]
- Pareek, A.; Kumar, R.; Mudgal, R.; Neetu, N.; Sharma, M.; Kumar, P.; Tomar, S. Alphavirus Antivirals Targeting RNA-Dependent RNA Polymerase Domain of NsP4 Divulged Using Surface Plasmon Resonance. FEBS J. 2022, 289, 4901–4924. [Google Scholar] [CrossRef]
- Rani, R.; Long, S.; Pareek, A.; Dhaka, P.; Singh, A.; Kumar, P.; McInerney, G.; Tomar, S. Multi-Target Direct-Acting SARS-CoV-2 Antivirals against the Nucleotide-Binding Pockets of Virus-Specific Proteins. Virology 2022, 577, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Rani, R.; Nehul, S.; Choudhary, S.; Upadhyay, A.; Kumar Sharma, G.; Kumar, P.; Tomar, S.; scientist, S. Revealing and Evaluation of Antivirals Targeting Multiple Druggable Sites of RdRp Complex in SARS-CoV-2. bioRxiv 2023. [Google Scholar] [CrossRef]
- Choi, K.H. Viral Polymerases. Adv. Exp. Med. Biol. 2012, 726, 267–304. [Google Scholar] [CrossRef]
- Liu, S.; Knafels, J.D.; Chang, J.S.; Waszak, G.A.; Baldwin, E.T.; Deibel, M.R.; Thomsen, D.R.; Homa, F.L.; Wells, P.A.; Tory, M.C.; et al. Crystal Structure of the Herpes Simplex Virus 1 DNA Polymerase. J. Biol. Chem. 2006, 281, 18193–18200. [Google Scholar] [CrossRef] [PubMed]
- Zarrouk, K.; Piret, J.; Boivin, G. Herpesvirus DNA Polymerases: Structures, Functions and Inhibitors. Virus Res. 2017, 234, 177–192. [Google Scholar] [CrossRef] [PubMed]
- Gustavsson, E.; Grünewald, K.; Elias, P.; Hällberg, B.M. Dynamics of the Herpes Simplex Virus DNA Polymerase Holoenzyme during DNA Synthesis and Proof-Reading Revealed by Cryo-EM. Nucleic Acids Res. 2024, 52, 7292–7304. [Google Scholar] [CrossRef]
- Shankar, S.; Pan, J.; Yang, P.; Bian, Y.; Oroszlán, G.; Yu, Z.; Mukherjee, P.; Filman, D.J.; Hogle, J.M.; Shekhar, M.; et al. Viral DNA Polymerase Structures Reveal Mechanisms of Antiviral Drug Resistance. Cell 2024, 187, 5572–5586. [Google Scholar] [CrossRef]
- D’Cruz, O.J.; Uckun, F.M. Dawn of Non-Nucleoside Inhibitor-Based Anti-HIV Microbicides. J. Antimicrob. Chemother. 2006, 57, 411–423. [Google Scholar] [CrossRef]
- Tuaillon, E.; Gueudin, M.; Lemée, V.; Gueit, I.; Roques, P.; Corrigan, G.E.; Plantier, J.C.; Simon, F.; Braun, J. Phenotypic susceptibility to nonnucleoside inhibitors of virion-associated reverse transcriptase from different HIV types and groups. JAIDS J. Acquir. Immune Defic. Syndr. 2024, 37, 1543–1549. [Google Scholar] [CrossRef]
- Smerdon, S.J.; Jäger, J.; Wang, J.; Kohlstaedt, L.A.; Chirino, A.J.; Friedman, J.M.; Rice, P.A.; Steitz, T.A. Structure of the Binding Site for Nonnucleoside Inhibitors of the Reverse Transcriptase of Human Immunodeficiency Virus Type 1. Proc. Natl. Acad. Sci. USA 1994, 91, 3911–3915. [Google Scholar] [CrossRef]
- Merluzzi, V.J.; Hargrave, K.D.; Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J.C.; Shih, C.-K.; Eckner, K.; Hattox, S.; Adams, J.; et al. Inhibition of HIV-1 Replication by a Nonnucleoside Reverse Transcriptase Inhibitor. Science 1990, 250, 1411–1413. [Google Scholar] [CrossRef] [PubMed]
- Omoto, S.; Speranzini, V.; Hashimoto, T.; Noshi, T.; Yamaguchi, H.; Kawai, M.; Kawaguchi, K.; Uehara, T.; Shishido, T.; Naito, A.; et al. Characterization of Influenza Virus Variants Induced by Treatment with the Endonuclease Inhibitor Baloxavir Marboxil. Sci. Rep. 2018, 8, 9633. [Google Scholar] [CrossRef]
- Chang, S.; Sun, D.; Liang, H.; Wang, J.; Li, J.; Guo, L.; Wang, X.; Guan, C.; Boruah, B.M.; Yuan, L.; et al. Cryo-EM Structure of Influenza Virus RNA Polymerase Complex at 4.3Å Resolution. Mol. Cell 2015, 57, 925–935. [Google Scholar] [CrossRef] [PubMed]
- Kirchdoerfer, R.N.; Ward, A.B. Structure of the SARS-CoV Nsp12 Polymerase Bound to Nsp7 and Nsp8 Co-Factors. Nat. Commun. 2019, 10, 2342. [Google Scholar] [CrossRef] [PubMed]
- FDA. Approves First Treatment for COVID-19|FDA. Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19 (accessed on 1 January 2025).
- Yin, W.; Mao, C.; Luan, X.; Shen, D.D.; Shen, Q.; Su, H.; Wang, X.; Zhou, F.; Zhao, W.; Gao, M.; et al. Structural Basis for Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir. Science 2020, 368, 1499–1504. [Google Scholar] [CrossRef] [PubMed]
- Elfiky, A.A. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp): A Molecular Docking Study. Life Sci. 2020, 253, 117592. [Google Scholar] [CrossRef]
- Sangawa, H.; Komeno, T.; Nishikawa, H.; Yoshida, A.; Takahashi, K.; Nomura, N.; Furuta, Y. Mechanism of Action of T-705 Ribosyl Triphosphate against Influenza Virus RNA Polymerase. Antimicrob. Agents Chemother. 2013, 57, 5202–5208. [Google Scholar] [CrossRef]
- Painter, G.R.; Natchus, M.G.; Cohen, O.; Holman, W.; Painter, W.P. Developing a Direct Acting, Orally Available Antiviral Agent in a Pandemic: The Evolution of Molnupiravir as a Potential Treatment for COVID-19. Curr. Opin. Virol. 2021, 50, 17–22. [Google Scholar] [CrossRef]
- Yoon, J.J.; Toots, M.; Lee, S.; Lee, M.E.; Ludeke, B.; Luczo, J.M.; Ganti, K.; Cox, R.M.; Sticher, Z.M.; Edpuganti, V.; et al. Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses. Antimicrob. Agents Chemother. 2018, 62, e01062-21. [Google Scholar] [CrossRef]
- Peng, Q.; Peng, R.; Yuan, B.; Wang, M.; Zhao, J.; Fu, L.; Qi, J.; Shi, Y. Structural Basis of SARS-CoV-2 Polymerase Inhibition by Favipiravir. Innovation 2021, 2, 100080. [Google Scholar] [CrossRef]
- Pommier, Y.; Johnson, A.A.; Marchand, C. Integrase Inhibitors to Treat HIV/AIDS. Nat. Rev. Drug Discov. 2005, 4, 236–248. [Google Scholar] [CrossRef] [PubMed]
- Cai, M.; Zheng, R.; Caffrey, M.; Craigie, R.; Marius Clore, G.; Gronenborn, A.M. Solution Structure of the N-Terminal Zinc Binding Domain of HIV-1 Integrase. Nat. Struct. Bio.l 1997, 4, 567–577. [Google Scholar] [CrossRef]
- Renzi, G.; Carta, F.; Supuran, C.T. The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario. Int. J. Mol. Sci. 2023, 24, 12187. [Google Scholar] [CrossRef] [PubMed]
- Maertens, G.N.; Engelman, A.N.; Cherepanov, P. Structure and Function of Retroviral Integrase. Nat Rev Microbiol. 2022, 20, 20–34. [Google Scholar] [CrossRef] [PubMed]
- Blanco, J.L.; Whitlock, G.; Milinkovic, A.; Moyle, G. HIV Integrase Inhibitors: A New Era in the Treatment of HIV. Expert Opin. Pharmacother. 2015, 16, 1313–1324. [Google Scholar] [CrossRef]
- Goldgur, Y.; Craigie, R.; Cohen, G.H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T.; Murai, H.; Davies, D.R. Structure of the HIV-1 Integrase Catalytic Domain Complexed with an Inhibitor: A Platform for Antiviral Drug Design. Proc. Natl. Acad. Sci. USA 1999, 96, 13040–13043. [Google Scholar] [CrossRef]
- Hare, S.; Smith, S.J.; Métifiot, M.; Jaxa-Chamiec, A.; Pommier, Y.; Hughes, S.H.; Cherepanov, P. Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572). Mol. Pharmacol. 2011, 80, 565–572. [Google Scholar] [CrossRef]
- Ballantyne, A.D.; Perry, C.M. Dolutegravir: First Global Approval. Drugs 2013, 73, 1627–1637. [Google Scholar] [CrossRef]
- New report documents increase in HIV drug resistance to dolutegravir|WHO. Available online: https://www.who.int/news/item/05-03-2024-new-report-documents-increase-in-hiv-drug-resistance-to-dolutegravir (accessed on 1 January 2025).
- Li, M.; Passos, D.O.; Shan, Z.; Smith, S.J.; Sun, Q.; Biswas, A.; Choudhuri, I.; Strutzenberg, T.S.; Haldane, A.; Deng, N.; et al. Mechanisms of HIV-1 Integrase Resistance to Dolutegravir and Potent Inhibition of Drug-Resistant Variants. Sci. Adv. 2023, 9, eadg5953. [Google Scholar] [CrossRef]
- Passos, D.O.; Li, M.; Jóźwik, I.K.; Zhao, X.Z.; Santos-Martins, D.; Yang, R.; Smith, S.J.; Jeon, Y.; Forli, S.; Hughes, S.H.; et al. Structural Basis for Strand-Transfer Inhibitor Binding to HIV Intasomes. Science 2020, 367, 810–814. [Google Scholar] [CrossRef]
- Bonnard, D.; Le Rouzic, E.; Eiler, S.; Amadori, C.; Orlov, I.; Bruneau, J.M.; Brias, J.; Barbion, J.; Chevreuil, F.; Spehner, D.; et al. Structure-Function Analyses Unravel Distinct Effects of Allosteric Inhibitors of HIV-1 Integrase on Viral Maturation and Integration. J. Biol. Chem. 2018, 293, 6172–6186. [Google Scholar] [CrossRef] [PubMed]
- Christ, F.; Voet, A.; Marchand, A.; Nicolet, S.; Desimmie, B.A.; Marchand, D.; Bardiot, D.; Van Der Veken, N.J.; Van Remoortel, B.; Strelkov, S.V.; et al. Rational Design of Small-Molecule Inhibitors of the LEDGF/P75-Integrase Interaction and HIV Replication. Nat. Chem. Biol. 2010, 6, 442–448. [Google Scholar] [CrossRef]
- Xie, Y.; Wu, L.; Wang, M.; Cheng, A.; Yang, Q.; Wu, Y.; Jia, R.; Zhu, D.; Zhao, X.; Chen, S.; et al. Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets. Front. Microbiol. 2019, 10, 941. [Google Scholar] [CrossRef] [PubMed]
- Brown, D.G.; Visse, R.; Sandhu, G.; Davies, A.; Rizkallah, P.J.; Melitz, C.; Summers, W.C.; Sanderson, M.R. Crystal Structures of the Thymidine Kinase from Herpes Simplex Virus Type-I in Complex with Deoxythymidine and Ganciclovir. Nat. Struct. Biol. 1995, 2, 876–881. [Google Scholar] [CrossRef] [PubMed]
- Wild, K.; Bohner, T.; Aubry, A.; Folkers, G.; Schulz, G.E. The Three-Dimensional Structure of Thymidine Kinase from Herpes Simplex Virus Type 1. FEBS Lett. 1995, 368, 289–292. [Google Scholar] [CrossRef]
- Frobert, E.; Ooka, T.; Cortay, J.C.; Lina, B.; Thouvenot, D.; Morfin, F. Herpes Simplex Virus Thymidine Kinase Mutations Associated with Resistance to Acyclovir: A Site-Directed Mutagenesis Study. Antimicrob. Agents Chemother. 2005, 49, 1055–1059. [Google Scholar] [CrossRef]
- Ramdhan, P.; Li, C. Targeting Viral Methyltransferases: An Approach to Antiviral Treatment for SsRNA Viruses. Viruses 2022, 14, 379. [Google Scholar] [CrossRef]
- Jones, R.; Bragagnolo, G.; Arranz, R.; Reguera, J. Capping Pores of Alphavirus NsP1 Gate Membranous Viral Replication Factories. Nature 2021, 589, 615–619. [Google Scholar] [CrossRef]
- Lampio, A.; Kilpeläinen, I.; Pesonen, S.; Karhi, K.; Auvinen, P.; Somerharju, P.; Kääriäinen, L. Membrane Binding Mechanism of an RNA Virus-Capping Enzyme. J. Biol. Chem. 2000, 275, 37853–37859. [Google Scholar] [CrossRef]
- Jones, R.; Hons, M.; Rabah, N.; Zamarreño, N.; Arranz, R.; Reguera, J. Structural Basis and Dynamics of Chikungunya Alphavirus RNA Capping by NsP1 Capping Pores. Proc. Natl. Acad. Sci. USA 2023, 120, e2213934120. [Google Scholar] [CrossRef]
- Bhutkar, M.; Saha, A.; Tomar, S. Viral Methyltransferase Inhibitors: Berbamine, Venetoclax, and Ponatinib as Efficacious Antivirals against Chikungunya Virus. Arch. Biochem. Biophys. 2024, 759, 110111. [Google Scholar] [CrossRef] [PubMed]
- Mudgal, R.; Bharadwaj, C.; Dubey, A.; Choudhary, S.; Nagarajan, P.; Aggarwal, M.; Ratra, Y.; Basak, S.; Tomar, S. Selective Estrogen Receptor Modulators Limit Alphavirus Infection by Targeting the Viral Capping Enzyme NsP1. Antimicrob. Agents Chemother. 2022, 66, e01943-21. [Google Scholar] [CrossRef] [PubMed]
- Mudgal, R.; Mahajan, S.; Tomar, S. Inhibition of Chikungunya Virus by an Adenosine Analog Targeting the SAM-Dependent NsP1 Methyltransferase. FEBS Lett. 2020, 594, 678–694. [Google Scholar] [CrossRef]
- Zhou, Y.; Ray, D.; Zhao, Y.; Dong, H.; Ren, S.; Li, Z.; Guo, Y.; Bernard, K.A.; Shi, P.-Y.; Li, H. Structure and Function of Flavivirus NS5 Methyltransferase. J. Virol. 2007, 81, 3891–3903. [Google Scholar] [CrossRef]
- Lim, S.P.; Sonntag, L.S.; Noble, C.; Nilar, S.H.; Ng, R.H.; Zou, G.; Monaghan, P.; Chung, K.Y.; Dong, H.; Liu, B.; et al. Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase. J. Biol. Chem. 2011, 286, 6233–6240. [Google Scholar] [CrossRef]
- Upadhyay, A.K.; Cyr, M.; Longenecker, K.; Tripathi, R.; Sun, C.; Kempf, D.J. Crystal Structure of Full-Length Zika Virus NS5 Protein Reveals a Conformation Similar to Japanese Encephalitis Virus NS5. Acta Crystallogr. Sect. F Struct. Biol. Commun. 2017, 73, 116–122. [Google Scholar] [CrossRef]
- Jia, H.; Zhong, Y.; Peng, C.; Gong, P. Crystal Structures of Flavivirus NS5 Guanylyltransferase Reveal a GMP-Arginine Adduct. J. Virol. 2022, 96, e00418-22. [Google Scholar] [CrossRef] [PubMed]
- Chen, H.; Lin, S.; Yang, F.; Chen, Z.; Guo, L.; Yang, J.; Lin, X.; Wang, L.; Duan, Y.; Wen, A.; et al. Structural and Functional Basis of Low-Affinity SAM/SAH-Binding in the Conserved MTase of the Multi-Segmented Alongshan Virus Distantly Related to Canonical Unsegmented Flaviviruses. PLoS Pathog. 2023, 19, e1011694. [Google Scholar] [CrossRef]
- Bhutkar, M.; Kumar, A.; Rani, R.; Singh, V.; Pathak, A.; Kothiala, A.; Mahajan, S.; Waghmode, B.; Kumar, R.; Mudgal, R.; et al. SAM-Dependent Viral MTase Inhibitors: Herbacetin and Caffeic Acid Phenethyl Ester, Structural Insights into Dengue MTase. bioRxiv 2024. bioRxiv:2022.05.31.494145. [Google Scholar] [CrossRef]
- García, L.L.; Padilla, L.; Castaño, J.C. Inhibitors Compounds of the Flavivirus Replication Process. Virol. J. 2017, 14, 95. [Google Scholar] [CrossRef]
- Benarroch, D.; Egloff, M.P.; Mulard, L.; Guerreiro, C.; Romette, J.L.; Canard, B. A Structural Basis for the Inhibition of the NS5 Dengue Virus MRNA 2′-O-Methyltransferase Domain by Ribavirin 5′-Triphosphate. J. Biol. Chem. 2004, 279, 35638–35643. [Google Scholar] [CrossRef] [PubMed]
- Milani, M.; Mastrangelo, E.; Bollati, M.; Selisko, B.; Decroly, E.; Bouvet, M.; Canard, B.; Bolognesi, M. Flaviviral Methyltransferase/RNA Interaction: Structural Basis for Enzyme Inhibition. Antivir. Res. 2009, 83, 28–34. [Google Scholar] [CrossRef] [PubMed]
- Nencka, R.; Silhan, J.; Klima, M.; Otava, T.; Kocek, H.; Krafcikova, P.; Boura, E. Coronaviral RNA-Methyltransferases: Function, Structure and Inhibition. Nucleic Acids Res. 2022, 50, 635–650. [Google Scholar] [CrossRef]
- Li, X.; Song, Y. Perspective for Drug Discovery Targeting SARS Coronavirus Methyltransferases: Function, Structure and Inhibition. J. Med. Chem. 2024, 67, 18642–18655. [Google Scholar] [CrossRef]
- Pyle, A.M. Translocation and Unwinding Mechanisms of RNA and DNA Helicases. Annu. Rev. Biophys. 2008, 37, 317–336. [Google Scholar] [CrossRef] [PubMed]
- Kolykhalov, A.A.; Mihalik, K.; Feinstone, S.M.; Rice, C.M. Hepatitis C Virus-Encoded Enzymatic Activities and Conserved RNA Elements in the 3′ Nontranslated Region Are Essential for Virus Replication In Vivo. J. Virol. 2000, 74, 2046–2051. [Google Scholar] [CrossRef]
- Jankowsky, E.; Gross, C.H.; Shuman, S.; Pyle, A.M. The DExH Protein NPH-II Is a Processive and Directional Motor for Unwinding RNA. Nature 2000, 403, 447–451. [Google Scholar] [CrossRef]
- Newman, J.A.; Douangamath, A.; Yadzani, S.; Yosaatmadja, Y.; Aimon, A.; Brandão-Neto, J.; Dunnett, L.; Gorrie-stone, T.; Skyner, R.; Fearon, D.; et al. Structure, Mechanism and Crystallographic Fragment Screening of the SARS-CoV-2 NSP13 Helicase. Nat. Commun. 2021, 12, 4848. [Google Scholar] [CrossRef]
- Smelkova, N.V.; Borowiec, J.A. Dimerization of Simian Virus 40 T-Antigen Hexamers Activates T-Antigen DNA Helicase Activity. J. Virol. 1997, 71, 8766–8773. [Google Scholar] [CrossRef]
- Hughes, F.J.; Romanos, M.A. E1 Protein of Human Papillomavirus Is a DNA Helicase/ATPase. Nucleic Acids Res. 1993, 21, 5817–5823. [Google Scholar] [CrossRef]
- Xu, T.; Sampath, A.; Chao, A.; Wen, D.; Nanao, M.; Chene, P.; Vasudevan, S.G.; Lescar, J. Structure of the Dengue Virus Helicase/Nucleoside Triphosphatase Catalytic Domain at a Resolution of 2.4 Å. J. Virol. 2005, 79, 10278–10288. [Google Scholar] [CrossRef] [PubMed]
- Zhang, W.; Liu, Y.; Yang, M.; Yang, J.; Shao, Z.; Gao, Y.; Jiang, X.; Cui, R.; Zhang, Y.; Zhao, X.; et al. Structural and Functional Insights into the Helicase Protein E5 of Mpox Virus. Cell Discov. 2024, 10, 67. [Google Scholar] [CrossRef] [PubMed]
- Law, Y.-S.; Wang, S.; Tan, Y.B.; Shih, O.; Utt, A.; Goh, W.Y.; Lian, B.-J.; Chen, M.W.; Jeng, U.-S.; Merits, A.; et al. Interdomain Flexibility of Chikungunya Virus NsP2 Helicase-Protease Differentially Influences Viral RNA Replication and Infectivity. J. Virol. 2021, 95, e01470-20. [Google Scholar] [CrossRef]
- Lou, Z.; Sun, Y.; Rao, Z. Current Progress in Antiviral Strategies. Trends Pharmacol. Sci. 2014, 35, 86–102. [Google Scholar] [CrossRef]
- Wu, J.; Bera, A.K.; Kuhn, R.J.; Smith, J.L. Structure of the Flavivirus Helicase: Implications for Catalytic Activity, Protein Interactions, and Proteolytic Processing. J. Virol. 2005, 79, 10268–10277. [Google Scholar] [CrossRef] [PubMed]
- Tortorici, M.A.; Duquerroy, S.; Kwok, J.; Vonrhein, C.; Perez, J.; Lamp, B.; Bricogne, G.; Rümenapf, T.; Vachette, P.; Rey, F.A. X-Ray Structure of the Pestivirus NS3 Helicase and Its Conformation in Solution. J. Virol. 2015, 89, 4356–4371. [Google Scholar] [CrossRef]
- Fang, X.; Lu, G.; Deng, Y.; Yang, S.; Hou, C.; Gong, P. Unusual Substructure Conformations Observed in Crystal Structures of a Dicistrovirus RNA-Dependent RNA Polymerase Suggest Contribution of the N-Terminal Extension in Proper Folding. Virol. Sin. 2023, 38, 531–540. [Google Scholar] [CrossRef]
- Anindita, P.D.; Halbeisen, M.; Řeha, D.; Tuma, R.; Franta, Z. Mechanistic Insight into the RNA-Stimulated ATPase Activity of Tick-Borne Encephalitis Virus Helicase. J. Biol. Chem. 2022, 298, 102383. [Google Scholar] [CrossRef]
- Shao, Z.; Su, S.; Yang, J.; Zhang, W.; Gao, Y.; Zhao, X.; Zhang, Y.; Shao, Q.; Cao, C.; Li, H.; et al. Structures and Implications of the C962R Protein of African Swine Fever Virus. Nucleic Acids Res. 2023, 51, 9475–9490. [Google Scholar] [CrossRef]
- Gu, M.; Rice, C.M. Three Conformational Snapshots of the Hepatitis C Virus NS3 Helicase Reveal a Ratchet Translocation Mechanism. Proc. Natl. Acad. Sci. USA 2010, 107, 521–528. [Google Scholar] [CrossRef]
- Hutin, S.; Ling, W.L.; Tarbouriech, N.; Schoehn, G.; Grimm, C.; Fischer, U.; Burmeister, W.P. The Vaccinia Virus DNA Helicase Structure from Combined Single-Particle Cryo-Electron Microscopy and AlphaFold2 Prediction. Viruses 2022, 14, 2206. [Google Scholar] [CrossRef] [PubMed]
- Liu, D.; Wang, Y.S.; Gesell, J.J.; Wyss, D.F. Solution Structure and Backbone Dynamics of an Engineered Arginine-Rich Subdomain 2 of the Hepatitis C Virus NS3 RNA Helicase. J. Mol. Biol. 2001, 314, 543–561. [Google Scholar] [CrossRef]
- Frick, D.; Lam, A. Understanding Helicases as a Means of Virus Control. Curr. Pharm. Des. 2006, 12, 1315–1338. [Google Scholar] [CrossRef] [PubMed]
- Tan, Q.; Zhu, Y.; Li, J.; Chen, Z.; Han, G.W.; Kufareva, I.; Li, T.; Ma, L.; Fenalti, G.; Li, J.; et al. Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex. Science 2013, 341, 1387–1390. [Google Scholar] [CrossRef]
- Wu, B.; Chien, E.Y.T.; Mol, C.D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.; Brooun, A.; Wells, P.; Bi, F.C.; et al. Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists. Science 2010, 330, 1066–1071. [Google Scholar] [CrossRef]
- Haqqani, A.A.; Tilton, J.C. Entry Inhibitors and Their Use in the Treatment of HIV-1 Infection. Antivir. Res. 2013, 98, 158–170. [Google Scholar] [CrossRef]
- Blair, H.A. Ibalizumab: A Review in Multidrug-Resistant HIV-1 Infection. Drugs 2020, 80, 189–196. [Google Scholar] [CrossRef]
- Freeman, M.M.; Seaman, M.S.; Rits-Volloch, S.; Hong, X.; Kao, C.Y.; Ho, D.D.; Chen, B. Crystal Structure of HIV-1 Primary Receptor CD4 in Complex with a Potent Antiviral Antibody. Structure 2010, 18, 1632–1641. [Google Scholar] [CrossRef] [PubMed]
- Bhutkar, M.; Singh, V.; Dhaka, P.; Tomar, S. Virus-Host Protein-Protein Interactions as Molecular Drug Targets for Arboviral Infections. Front. Virol. 2022, 2, 959586. [Google Scholar] [CrossRef]
- Mahajan, S.; Choudhary, S.; Kumar, P.; Tomar, S. Antiviral Strategies Targeting Host Factors and Mechanisms Obliging +ssRNA Viral Pathogens. Bioorg. Med. Chem. 2021, 46, 116356. [Google Scholar] [CrossRef]
- Dhaka, P.; Singh, A.; Nehul, S.; Choudhary, S.; Panda, P.K.; Sharma, G.K.; Kumar, P.; Tomar, S. Disruption of Molecular Interactions between the G3BP1 Stress Granule Host Protein and the Nucleocapsid (NTD-N) Protein Impedes SARS-CoV-2 Virus Replication. Biochemistry 2024, 64, 823–840. [Google Scholar] [CrossRef]
- Mahajan, S.; Kumar, R.; Singh, A.; Pareek, A.; Kumar, P.; Tomar, S. Targeting the Host Protein G3BP1 for the Discovery of Novel Antiviral Inhibitors against Chikungunya Virus. bioRxiv 2024. bioRxiv:2022.11.11.516135. [Google Scholar] [CrossRef]
- De Chassey, B.; Meyniel-Schicklin, L.; Aublin-Gex, A.; André, P.; Lotteau, V. New Horizons for Antiviral Drug Discovery from Virus–Host Protein Interaction Networks. Curr. Opin. Virol. 2012, 2, 606–613. [Google Scholar] [CrossRef] [PubMed]
- Idrees, S.; Chen, H.; Panth, N.; Paudel, K.R.; Hansbro, P.M. Exploring Viral–Host Protein Interactions as Antiviral Therapies: A Computational Perspective. Microorganisms 2024, 12, 630. [Google Scholar] [CrossRef]
- Idrees, S.; Paudel, K.R.; Sadaf, T.; Hansbro, P.M. How Different Viruses Perturb Host Cellular Machinery via Short Linear Motifs. EXCLI J. 2023, 22, 1113–1128. [Google Scholar] [CrossRef] [PubMed]
- de Chassey, B.; Meyniel-Schicklin, L.; Vonderscher, J.; André, P.; Lotteau, V. Virus-Host Interactomics: New Insights and Opportunities for Antiviral Drug Discovery. Genome Med. 2014, 6, 115. [Google Scholar] [CrossRef]
- Brito, A.F.; Pinney, J.W. Protein-Protein Interactions in Virus-Host Systems. Front. Microbiol. 2017, 8, 01557. [Google Scholar] [CrossRef] [PubMed]
- Kumar, N.; Sharma, S.; Kumar, R.; Tripathi, B.N.; Barua, S.; Ly, H.; Rouse, B.T. Host-Directed Antiviral Therapy. Clin. Microbiol. Rev. 2020, 33, e00168-19. [Google Scholar] [CrossRef]
- Eslami, N.; Aghbash, P.S.; Shamekh, A.; Entezari-Maleki, T.; Nahand, J.S.; Sales, A.J.; Baghi, H.B. SARS-CoV-2: Receptor and Co-Receptor Tropism Probability. Curr. Microbiol. 2022, 79, 133. [Google Scholar] [CrossRef]
- Baggen, J.; Vanstreels, E.; Jansen, S.; Daelemans, D. Cellular Host Factors for SARS-CoV-2 Infection. Nat. Microbiol. 2021, 6, 1219–1232. [Google Scholar] [CrossRef]
- Lee, M.F.; Wu, Y.S.; Poh, C.L. Molecular Mechanisms of Antiviral Agents against Dengue Virus. Viruses 2023, 15, 705. [Google Scholar] [CrossRef] [PubMed]
- Anwar, M.N.; Akhtar, R.; Abid, M.; Khan, S.A.; Rehman, Z.U.; Tayyub, M.; Malik, M.I.; Shahzad, M.K.; Mubeen, H.; Qadir, M.S.; et al. The Interactions of Flaviviruses with Cellular Receptors: Implications for Virus Entry. Virology 2022, 568, 77–85. [Google Scholar] [CrossRef] [PubMed]
- Li, H.; Huang, Q.Z.; Zhang, H.; Liu, Z.X.; Chen, X.H.; Ye, L.L.; Luo, Y. The Land-Scape of Immune Response to Monkeypox Virus. EBioMedicine 2023, 87, 104424. [Google Scholar] [CrossRef]
- Chakraborty, C.; Sharma, A.R.; Bhattacharya, M.; Lee, S.S. A Detailed Overview of Immune Escape, Antibody Escape, Partial Vaccine Escape of SARS-CoV-2 and Their Emerging Variants With Escape Mutations. Front. Immunol. 2022, 13, 801522. [Google Scholar] [CrossRef]
- Lemaitre, J.C.; Grantz, K.H.; Kaminsky, J.; Meredith, H.R.; Truelove, S.A.; Lauer, S.A.; Keegan, L.T.; Shah, S.; Wills, J.; Kaminsky, K.; et al. A Scenario Modeling Pipeline for COVID-19 Emergency Planning. Sci. Rep. 2021, 11, 7534. [Google Scholar] [CrossRef]
- Crucitti, D.; Pérez Míguez, C.; Ángel, J.; Arias, D.; Beltrá, D.; Prada, F.; Orgueira, A.M. De Novo Drug Design through Artificial Intelligence: An Introduction. Front. Hematol. 2024, 3, 1305741. [Google Scholar] [CrossRef]
- Floresta, G.; Zagni, C.; Patamia, V.; Rescifina, A. How Can Artificial Intelligence Be Utilized for de Novo Drug Design against COVID-19 (SARS-CoV-2)? Expert Opin. Drug Discov. 2023, 18, 1061–1064. [Google Scholar] [CrossRef]
- Patel, C.N.; Mall, R.; Bensmail, H. AI-Driven Drug Repurposing and Binding Pose Meta Dynamics Identifies Novel Targets for Monkeypox Virus. J. Infect. Public Health 2023, 16, 799–807. [Google Scholar] [CrossRef] [PubMed]
- Slater, A.; Nair, N.; Suétt, R.; Mac Donnchadha, R.; Bamford, C.; Jasim, S.; Livingstone, D.; Hutchinson, E. Visualising Viruses. J. Gen. Virol. 2022, 103, 001730. [Google Scholar] [CrossRef]
- Lu, Y.; Yang, Q.; Ran, T.; Zhang, G.; Li, W.; Zhou, P.; Tang, J.; Dai, M.; Zhong, J.; Chen, H.; et al. Discovery of Orally Bioavailable SARS-CoV-2 Papain-like Protease Inhibitor as a Potential Treatment for COVID-19. Nat. Commun. 2024, 15, 10169. [Google Scholar] [CrossRef]
- Turzynski, V.; Monsees, I.; Moraru, C.; Probst, A.J. Imaging Techniques for Detecting Prokaryotic Viruses in Environmental Samples. Viruses 2021, 13, 2126. [Google Scholar] [CrossRef]
- Rut, W.; Lv, Z.; Zmudzinski, M.; Patchett, S.; Nayak, D.; Snipas, S.J.; El Oualid, F.; Huang, T.T.; Bekes, M.; Drag, M.; et al. Activity Profiling and Crystal Structures of Inhibitor-Bound SARS-CoV-2 Papain-like Protease: A Framework for Anti–COVID-19 Drug Design. Sci. Adv. 2020, 6, 4596–4612. [Google Scholar] [CrossRef] [PubMed]
- Greasley, S.E.; Noell, S.; Plotnikova, O.; Ferre, R.A.; Liu, W.; Bolanos, B.; Fennell, K.; Nicki, J.; Craig, T.; Zhu, Y.; et al. Structural Basis for the in Vitro Efficacy of Nirmatrelvir against SARS-CoV-2 Variants. J. Biol. Chem. 2022, 298, 101972. [Google Scholar] [CrossRef] [PubMed]
- Feng, Q.; Cheng, K.; Zhang, L.; Wang, D.; Gao, X.; Liang, J.; Liu, G.; Ma, N.; Xu, C.; Tang, M.; et al. Rationally Designed Multimeric Nanovaccines Using Icosahedral DNA Origami for Display of SARS-CoV-2 Receptor Binding Domain. Nat. Commun. 2024, 15, 9581. [Google Scholar] [CrossRef] [PubMed]
- Dokhale, S.; Garse, S.; Devarajan, S.; Thakur, V.; Kolhapure, S. Rational Design of Antiviral Therapeutics. Comput. Methods Ration. Drug Des. 2025, 423–443. [Google Scholar] [CrossRef]
- Al-Amran, F.G.; Hezam, A.M.; Rawaf, S.; Yousif, M.G. Genomic Analysis and Artificial Intelligence: Predicting Viral Mutations and Future Pandemics. arXiv 2023, arXiv:2309.15936. [Google Scholar] [CrossRef]
- Parvatikar, P.P.; Patil, S.; Khaparkhuntikar, K.; Patil, S.; Singh, P.K.; Sahana, R.; Kulkarni, R.V.; Raghu, A.V. Artificial Intelligence: Machine Learning Approach for Screening Large Database and Drug Discovery. Antivir. Res 2023, 220, 105740. [Google Scholar] [CrossRef]
- KP Jayatunga, M.; Ayers, M.; Bruens, L.; Jayanth, D.; Meier, C. How Successful Are AI-Discovered Drugs in Clinical Trials? A First Analysis and Emerging Lessons. Drug. Discov. Today 2024, 29, 104009. [Google Scholar] [CrossRef]
- Mouchlis, V.D.; Afantitis, A.; Serra, A.; Fratello, M.; Papadiamantis, A.G.; Aidinis, V.; Lynch, I.; Greco, D.; Melagraki, G. Advances in De Novo Drug Design: From Conventional to Machine Learning Methods. Int. J. Mol. Sci. 2021, 22, 1676. [Google Scholar] [CrossRef]
- Atz, K.; Cotos, L.; Isert, C.; Håkansson, M.; Focht, D.; Hilleke, M.; Nippa, D.F.; Iff, M.; Ledergerber, J.; Schiebroek, C.C.G.; et al. Prospective de Novo Drug Design with Deep Interactome Learning. Nat. Commun. 2024, 15, 3408. [Google Scholar] [CrossRef]
- Singh, V.; Bhutkar, M.; Choudhary, S.; Nehul, S.; Kumar, R.; Singla, J.; Kumar, P.; Tomar, S. Structure-Guided Mutations in CDRs for Enhancing the Affinity of Neutralizing SARS-CoV-2 Nanobody. Biochem. Biophys. Res. Commun. 2024, 734, 150746. [Google Scholar] [CrossRef] [PubMed]
- Singh, V.; Choudhary, S.; Bhutkar, M.; Nehul, S.; Ali, S.; Singla, J.; Kumar, P.; Tomar, S. Designing and Bioengineering of CDRs with Higher Affinity against Receptor-Binding Domain (RBD) of SARS-CoV-2 Omicron Variant 2024. Int. J. Biol. Macromol. 2025, 290, 138751. [Google Scholar] [CrossRef] [PubMed]
- Sinha, S.; Vegesna, R.; Mukherjee, S.; Kammula, A.V.; Dhruba, S.R.; Wu, W.; Kerr, D.L.; Nair, N.U.; Jones, M.G.; Yosef, N.; et al. PERCEPTION Predicts Patient Response and Resistance to Treatment Using Single-Cell Transcriptomics of Their Tumors. Nature Cancer 2024, 5, 938–952. [Google Scholar] [CrossRef]
- Mak, K.-K.; Wong, Y.-H.; Pichika, M.R. Artificial Intelligence in Drug Discovery and Development. In Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays; Springer International: Cham, Switzerland, 2024; pp. 1461–1498. [Google Scholar] [CrossRef]
- He, H.; He, B.; Guan, L.; Zhao, Y.; Jiang, F.; Chen, G.; Zhu, Q.; Chen, C.Y.C.; Li, T.; Yao, J. De Novo Generation of SARS-CoV-2 Antibody CDRH3 with a Pre-Trained Generative Large Language Model. Nat. Commun. 2024, 15, 6867. [Google Scholar] [CrossRef]
- Dunbar, J.; Krawczyk, K.; Leem, J.; Marks, C.; Nowak, J.; Regep, C.; Georges, G.; Kelm, S.; Popovic, B.; Deane, C.M. SAbPred: A Structure-Based Antibody Prediction Server. Nucleic Acids Res. 2016, 44, W474–W478. [Google Scholar] [CrossRef]
- Caradonna, T.M.; Schmidt, A.G. Protein Engineering Strategies for Rational Immunogen Design. npj Vaccines 2021, 6, 154. [Google Scholar] [CrossRef] [PubMed]
- Marcandalli, J.; Fiala, B.; Ols, S.; Perotti, M.; de van der Schueren, W.; Snijder, J.; Hodge, E.; Benhaim, M.; Ravichandran, R.; Carter, L.; et al. Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus. Cell 2019, 176, 1420–1431.e17. [Google Scholar] [CrossRef]
- Shanehsazzadeh, A.; McPartlon, M.; Kasun, G.; Steiger, A.K.; Sutton, J.M.; Yassine, E.; McCloskey, C.; Haile, R.; Shuai, R.; Alverio, J.; et al. Unlocking de Novo Antibody Design with Generative Artificial Intelligence. bioRxiv 2024. bioRxiv:2023.01.08.523187. [Google Scholar] [CrossRef]
- Jumper, J.; Evans, R.; Pritzel, A.; Green, T.; Figurnov, M.; Ronneberger, O.; Tunyasuvunakool, K.; Bates, R.; Žídek, A.; Potapenko, A.; et al. Highly Accurate Protein Structure Prediction with AlphaFold. Nature 2021, 596, 583–589. [Google Scholar] [CrossRef]
- Watson, J.L.; Juergens, D.; Bennett, N.R.; Trippe, B.L.; Yim, J.; Eisenach, H.E.; Ahern, W.; Borst, A.J.; Ragotte, R.J.; Milles, L.F.; et al. De Novo Design of Protein Structure and Function with RFdiffusion. Nature 2023, 620, 1089–1100. [Google Scholar] [CrossRef]
- Mohan, S.; Kerry, P.S.; Bance, N.; Niikura, M.; Pinto, B.M. Serendipitous Discovery of a Potent Influenza Virus A Neuraminidase Inhibitor. Angew. Chem. Int. Ed. 2014, 53, 1076–1080. [Google Scholar] [CrossRef] [PubMed]
- Yuan, M.; Zhu, X.; He, W.T.; Zhou, P.; Kaku, C.I.; Capozzola, T.; Zhu, C.Y.; Yu, X.; Liu, H.; Yu, W.; et al. A Broad and Potent Neutralization Epitope in SARS-Related Coronaviruses. Proc. Natl. Acad. Sci. USA 2022, 119, e2205784119. [Google Scholar] [CrossRef] [PubMed]
- Walls, A.C.; Fiala, B.; Schäfer, A.; Wrenn, S.; Pham, M.N.; Murphy, M.; Tse, L.V.; Shehata, L.; O’Connor, M.A.; Chen, C.; et al. Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2. Cell 2020, 183, 1367–1382.e17. [Google Scholar] [CrossRef]
- Brouwer, P.J.M.; Antanasijevic, A.; Ronk, A.J.; Müller-Kräuter, H.; Watanabe, Y.; Claireaux, M.; Perrett, H.R.; Bijl, T.P.L.; Grobben, M.; Umotoy, J.C.; et al. Lassa Virus Glycoprotein Nanoparticles Elicit Neutralizing Antibody Responses and Protection. Cell Host Microbe 2022, 30, 1759–1772.e12. [Google Scholar] [CrossRef]
- Sesterhenn, F.; Yang, C.; Bonet, J.; Cramer, J.T.; Wen, X.; Wang, Y.; Chiang, C.I.; Abriata, L.A.; Kucharska, I.; Castoro, G.; et al. De Novo Protein Design Enables the Precise Induction of RSV-Neutralizing Antibodies. Science 2020, 368, eaay5051. [Google Scholar] [CrossRef] [PubMed]
- Mousa, J.J.; Sauer, M.F.; Sevy, A.M.; Finn, J.A.; Bates, J.T.; Alvarado, G.; King, H.G.; Loerinc, L.B.; Fong, R.H.; Doranz, B.J.; et al. Structural Basis for Nonneutralizing Antibody Competition at Antigenic Site II of the Respiratory Syncytial Virus Fusion Protein. Proc. Natl. Acad. Sci. USA 2016, 113, E6849–E6858. [Google Scholar] [CrossRef]
- Baum, A.; Fulton, B.O.; Wloga, E.; Copin, R.; Pascal, K.E.; Russo, V.; Giordano, S.; Lanza, K.; Negron, N.; Ni, M.; et al. Antibody Cocktail to SARS-CoV-2 Spike Protein Prevents Rapid Mutational Escape Seen with Individual Antibodies. Science 2020, 369, 1014–1018. [Google Scholar] [CrossRef] [PubMed]
- Chen, P.; Behre, G.; Hebert, C.; Kumar, P.; Farmer MacPherson, L.; Graham-Clarke, P.L.; De La Torre, I.; Nichols, R.M.; Hufford, M.M.; Patel, D.R.; et al. Bamlanivimab and Etesevimab Improve Symptoms and Associated Outcomes in Ambulatory Patients at Increased Risk for Severe Coronavirus Disease 2019: Results From the Placebo-Controlled Double-Blind Phase 3 BLAZE-1 Trial. Open Forum Infect. Dis. 2022, 9, ofac172. [Google Scholar] [CrossRef]
- Dong, J.; Zost, S.J.; Greaney, A.J.; Starr, T.N.; Dingens, A.S.; Chen, E.C.; Chen, R.E.; Case, J.B.; Sutton, R.E.; Gilchuk, P.; et al. Genetic and Structural Basis for SARS-CoV-2 Variant Neutralization by a Two-Antibody Cocktail. Nat. Microbiol. 2021, 6, 1233–1244. [Google Scholar] [CrossRef]
- Focosi, D.; Casadevall, A.; Franchini, M.; Maggi, F. Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants. Viruses 2024, 16, 217. [Google Scholar] [CrossRef]
- Vishweshwaraiah, Y.L.; Hnath, B.; Rackley, B.; Wang, J.; Gontu, A.; Chandler, M.; Afonin, K.A.; Kuchipudi, S.V.; Christensen, N.; Yennawar, N.H.; et al. Adaptation-Proof SARS-CoV-2 Vaccine Design. Adv. Funct. Mater. 2022, 32, 2206055. [Google Scholar] [CrossRef] [PubMed]
- Liu, Q.; Lu, Y.; Cai, C.; Huang, Y.; Zhou, L.; Guan, Y.; Fu, S.; Lin, Y.; Yan, H.; Zhang, Z.; et al. A Broad Neutralizing Nanobody against SARS-CoV-2 Engineered from an Approved Drug. Cell Death Dis. 2024, 15, 458. [Google Scholar] [CrossRef] [PubMed]
- World Health Organization. Pathogens Prioritization: A Scientific Framework for Epidemic and Pandemic Research Preparedness; World Health Organization: Geneva, Switzerland, 2024. [Google Scholar]
- Bardhan, M.; Ray, I.; Roy, S.; Roy, P.; Thanneeru, P.; Twayana, A.R.; Prasad, S.; Bardhan, M.; Anand, A. Disease X and COVID-19: Turning Lessons from India and the World into Policy Recommendations. Ann. Med. Surg. 2024, 86, 5914–5921. [Google Scholar] [CrossRef] [PubMed]
Enveloped Glycoprotein | ||||||
---|---|---|---|---|---|---|
Protein Name | Virus (Family) | Name of Therapeutic | Type | Brand Name | Experimental Method | PDB ID |
N1 neuraminidase | Influenza A Virus (Orthomyxoviridae) | Zanamivir | Antiviral | Relenza | X-ray diffraction | 3CKZ, |
N8 neuraminidase | Influenza A Virus (Orthomyxoviridae) | Zanamivir | Antiviral | Relenza | X-ray diffraction | 2HTQ |
N1 Neuraminidase | Influenza A Virus (Orthomyxoviridae) | Oseltamivir | Antiviral | Tamiflu | X-ray diffraction | 3CL0, 2HU4 |
Hemagglutinin (HA) | Influenza A Virus (Orthomyxoviridae) | Umifenovir | Antiviral | Arbidol | X-ray diffraction | 5T6N, 5T6S |
Neuraminidase (NA) | Influenza A Virus (Orthomyxoviridae) | Laninamivir octanoate | Antiviral | Inavira | X-ray diffraction | 3TI4 |
N8 neuraminidase | Influenza A Virus (Orthomyxoviridae) | Peramivir | Antiviral | Rapivab | X-ray diffraction | 2HTU |
Glycoprotein 120 | HIV-1 (Retroviridae) | 412d | Antibody (Human) | N/A | X-ray diffraction | 2QAD |
glycoprotein (GP) trimer | Ebola virus (Filoviridae) | Atoltivimab, maftivimab and odesivimab | Antibody (Human) | Inmazeb (REGN-EB3) | Cryo-EM | 7TN9 |
glycoprotein (GP) trimer | Ebola virus (Filoviridae) | mAb100 and mAb114 | Antibody (Human) | Ansuvimab | X-ray diffraction | 5FHC |
Spike protein (S) | SARS-CoV-2 (Coronaviridae) | LY-CoV555 | Antibody (Human) | Bamlanivimab | X-ray diffraction | 7KMG |
Spike RBD | SARS-CoV-2 (Coronaviridae) | Ly-Cov1404 | Antibody (Human) | Bebtelovimab | X-ray diffraction | 7MMO |
Spike RBD | SARS-CoV-2 (Coronaviridae) | azd8895 and azd1061 | Antibody (Human) | Cilgavimab | X-ray diffraction | 7L7E |
Spike RBD | SARS-CoV-2 (Coronaviridae) | CA1 and CB6 | Antibody (Human) | Etesevimab | X-ray diffraction | 7C01 |
Spike RBD | SARS-CoV-2 (Coronaviridae) | REGN10933 and REGN10987 | Antibody (Human) | Masavibart | Cryo-EM | 6XDG |
Spike RBD | SARS-CoV-2 (Coronaviridae) | Ct-P59 | Antibody (Human) | Regdanvimab | X-ray diffraction | 7CM4 |
Spike RBD | SARS-CoV-2 (Coronaviridae) | GAR05 and GAR12 | Antibody (Human) | Sotrovimab | X-ray diffraction | 7T72 |
Spike RBD | SARS-CoV-2 (Coronaviridae) | DMAbs 2130 and DMAbs 2196 | Antibody (Human) | Tixagevimab | Cryo-EM | 8D8Q |
Spike protein (S) | SARS-CoV-2 (Coronaviridae) | REGN10933 and REGN10987 | Antibody (Human) | REGEN-COV | X-ray diffraction | 7M42 |
Fusion Glycoprotein (F) | Respiratory syncytial virus (RSV) | MEDI8897 | Antibody (Human) | Palivizumab | X-ray diffraction | 5UDC |
gp41 subunit (Envelope glycoprotein) | HIV-1 | T20 | Peptide | Enfuvirtide | X-ray diffraction | 5ZCX |
Capsid Protein | ||||||
Protein Name | Virus (Family) | Name of Therapeutic | Type | Brand Name | Experimental Method | PDB ID |
HBV Capsid | hepatitis B virus (HBV) (Picornaviridae) | Lenacapavir (DBT1) | Antiviral | Sunlenca | Cryo-EM | 6WFS |
HBV capsid assembly | hepatitis B virus (HBV) (Picornaviridae) | AT-130 | Antiviral | - | X-ray diffraction | 4G93 |
HBV capsid assembly | hepatitis B virus (HBV) (Picornaviridae) | HAP18 | Antiviral | - | X-ray diffraction | 5D7Y |
Membrane Proteins | ||||||
Protein Name | Virus (Family) | Name of Therapeutic | Type | Brand Name | Experimental Method | PDB ID |
Membrane protein (M2) | Influenza A Virus (Orthomyxoviridae) | Amantadineb | Antiviral | - | X-ray diffraction | 3C9J |
Membrane protein (M2) | Influenza A Virus (Orthomyxoviridae) | Rimantadine | Antiviral | Flumadine | X-ray diffraction | 6BKL, 6US9 |
Viral Replication Enzymes | ||||||
---|---|---|---|---|---|---|
Target Protein | Virus (Family) | Drug | Brand Name | Experimental Method | PDB ID | |
Protease | HIV protease | HIV-1 and HIV-2 (Retroviridae) | Saquinavir (SQV) | Invirase a | X-ray diffraction | 1HXB |
Ritonavir (RTV) | Norvir | X-ray diffraction | 1HXW | |||
Indinavir (IDV) | Crixivan a | X-ray diffraction | 1HSG | |||
Nelfinavir (NFV) | Viracept | X-ray diffraction | 1OHR | |||
Lopinavir (LPV) | Kaletra, (combination with ritonavir) | X-ray diffraction | 1MUI | |||
Atazanavir (ATV) | Reyataz | X-ray diffraction | 2AQU | |||
Darunavir (DRV) | Prezista | X-ray diffraction | 1T3R | |||
HIV-1 (Retroviridae) | Amprenavir (APV) | Agenerase a | X-ray diffraction | 1HPV | ||
Neutron diffraction | 4JEC | |||||
Tipranavir (TPV) | Aptivus | X-ray diffraction | 1D4S | |||
HCV NS3/4A protease | HCV genotype 1 (Flaviviridae) | Telaprevir (TVR) | Incivek a | X-ray diffraction | 3SV6 | |
Boceprevir (BOC) | Victrelis a | X-ray diffraction | 3LOX | |||
Simeprevir (SMV) | Olysio a | X-ray diffraction | 3KEE | |||
Vaniprevir (VPV) | Vanihep, in combination with ribavirin + PegIFNα-2b | X-ray diffraction | 3SU3 | |||
HCV genotype 1 and 4 (Flaviviridae) | Asunaprevir (ASV) | Sunvepra b | X-ray diffraction | 4WF8 | ||
Grazoprevir (GZR) | Zepatier | X-ray diffraction | 3SUD | |||
HCV genotype 1 to 4 (Flaviviridae) | Voxilaprevir (VOX) | Vosevi | X-ray diffraction | 6NZT | ||
Glecaprevir (GLE) | Mavyret | X-ray diffraction | 6P6L | |||
Main proteases (M pro or 3-chymotrypsin-like proteases (3CL pro) | SARS-CoV-2 (Coronaviridae) | Nirmatrelvir (NMV) | Paxlovid (combination with ritonavir) | X-ray diffraction | 7SI9 | |
Ensitrelvir (ENS) | Xocova b | X-ray diffraction | 7VU6 | |||
Polymerase | DNA-dependent DNA polymerase (DdDp) | HSV (Herpesviridae) | Foscarnet (PFA) | Foscavir | Cryo-EM | 8EXX |
Acyclovir (ACV) | Zovirax | Cryo-EM | 8V1T | |||
Reverse Transcriptase (RT) | HIV-1 and HIV-2 (Retroviridae) | Stavudine (d4T) | Zerit a | X-ray diffraction | 6AMO | |
Lamivudine (3TC) | Epivir, Combivir (combination with Zidovudine), Trizivir (combination with Zidovudine and abacavir) | X-ray diffraction | 6KDJ | |||
Tenofovir disoproxil fumarate (TDF) | Viread | X-ray diffraction | 1T05 | |||
Doravirine (DOR) | Pifeltro | X-ray diffraction | 4NCG | |||
Cryo-EM | 7Z2G | |||||
HIV-1 (Retroviridae) | Nevirapine (NVP) | Nevirapine (generic) | X-ray diffraction | 1FKP | ||
Cryo-EM | 7KJX | |||||
Delavirdine (DLV) | Rescriptor a | X-ray diffraction | 1KLM | |||
Efavirenz (EFV) | Efavirenz (generic) | X-ray diffraction | 1FK9 | |||
Cryo-EM | 7KJW | |||||
Etravirine (ETR) | Intelence | X-ray diffraction | 1SV5 | |||
Rilpivirine (RPV) | Edurant | X-ray diffraction | 2ZD1 | |||
Cryo-EM | 7Z2D | |||||
Dapivirine (DPV) | DapiRing b | X-ray diffraction | 1S6Q | |||
RNA-dependent RNA polymerase (RdRp) | Influenza A and B viruses (Orthomyxoviridae) | Baloxavir (BXA) | Xofluza | X-ray diffraction | 6FS6 | |
SARS-CoV-2 (Coronaviridae) | Remdesivir (RDV) | Veklury | Cryo-EM | 7BV2 | ||
Molnupiravir (MOV) | Lagevrio b,c | Cryo-EM | 7OZU | |||
Favipiravir (FVP) | Avigan b | Cryo-EM | 7CTT | |||
Integrase (IN) | Retroviral IN | HIV-1 and HIV-2 (Retroviridae) | Dolutegravir (DTG) | Tivicay, Triumeq (combination), Dutrebis (combination) | X-ray diffraction | 3S3M |
Cryo-EM | 8FN7 | |||||
Bictegravir (BIC) | Biktarvy (combination) | Cryo-EM | 6PUW | |||
Thymidine kinase (TK) | HSV-1 TK | HSV-1 (Herpesviridae) | Idoxuridine (IDU) -5-substituted 2′-deoxyuridine analog, substrate of TK | Dendrid | X-ray diffraction | 1KI7 |
Brivudine (BVDU) 5-substituted 2′-deoxyuridine analog, substrate of TK | Zostex b | X-ray diffraction | 1KI8 | |||
HSV (Herpesviridae) | Penciclovir (PCV) | Denavir | X-ray diffraction | 1KI3 | ||
Acyclovir (ACV) | Zovirax | X-ray diffraction | 2KI5 | |||
VZV TK | VZV (Herpesviridae) | Brivudine (BVDU) 5-substituted 2′-deoxyuridine analog, substrate of TK | Zostex b | X-ray diffraction | 1OSN |
Name of Therapeutic | Target Virus (Family) | Rational Designing Approach and Result | Type | PDB | Ref. |
---|---|---|---|---|---|
Nirmatrelvir | SARS-CoV-2 | A protease inhibitor for SARS-CoV-2 with reported protein–ligand complex, demonstrating its binding to the viral main protease (Mpro), which is crucial for viral replication. | Ligand | 7TLL | [298] |
Spirolactam | Influenza A | Carbocyclic analog of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3-pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay | Ligand | 4MJV | [317] |
VIR 250 and VIR 251 | SARS-CoV-2 | Designed and biochemically characterized potent inhibitors (VIR250 and VIR251) harboring high selectivity for SARS-CoV-2 PLpro and the related SARS-CoV-1 PLpro versus other proteases. | Peptide | 6WUU, 6WX4 | [297] |
Adintrevimab | SARS-CoV-2 | The crystallizable fragment (Fc) region of adintrevimab undergoes affinity maturation, leading to two amino acid modifications (S52A and W100B) that enhance the half-life while preserving the normal effector functions of IgG1. | Antibody | 7U2E | [318] |
RBD-I53-50 nanoparticles | SARS-CoV-2 | The nanoparticle vaccines present 60 SARS-CoV-2 spike receptor-binding domains (RBDs) were arranged in a highly immunogenic configuration, yielding neutralizing antibody titers tenfold greater than those elicited by the prefusion-stabilized spike, even when administered at a fivefold lower dosage. | Nanoparticle Vaccine | - | [319] |
ICO-RBD nanovaccine | SARS-CoV-2 | The immunogenicity of nanovaccines aimed at viral components, including the SARS-CoV-2 receptor-binding domain (RBD), is improved by multivalent antigen presentation on nanoparticles. Using icosahedral DNA origami (ICO) as a display particle, we achieve virus-like morphology and diameter for RBD nanovaccines. | Nanoparticle Vaccine | - | [299] |
GPC-I53-50NP | Lassa virus (LASV) | The study employs two-component protein nanoparticles to stabilize the Lassa virus glycoprotein complex (GPC) in its trimeric form. These nanoparticles elicited robust antibody responses in rabbits and provided protection to guinea pigs against lethal LASV challenge experiments. | Nanoparticle Vaccine | 7SGE | [320] |
D25 | Respiratory syncytial virus (RSV) | To elicit robust and specific neutralizing antibodies (nAbs), immunogens were designed with a focus on the epitopes derived from the prefusion structure of the respiratory syncytial virus (RSV) fusion protein. | Antibody | - | [321] |
DS-Cav1-I53-50 | Respiratory syncytial virus (RSV) | The approach involves presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. This two-component nanoparticle scaffold enables the production of highly ordered monodisperse immunogens that display DS-Cav1 at controllable density. | Nanoparticle Vaccine | - | [313] |
Fab 14N4 | Respiratory syncytial virus (RSV) | Palivizumab is a humanized monoclonal antibody derived from a murine mAb, designed to target antigenic site II of the RSV fusion (F) protein, a critical target in vaccine development. | Antibody | 5J3D | [322] |
Casirivimab and Imdevimab | SARS-CoV-2 | This cocktail, targeting the SARS-CoV-2 spike protein‘s receptor-binding domain, received Emergency Use Authorization (EUA) from the FDA in November 2020 for COVID-19 treatment, effectively preventing viral mutation escape. | Antibody | 6XDG | [323] |
Bamlanivimab and Etesevimab | SARS-CoV-2 | A combination targeting the SARS-CoV-2 spike protein was granted EUA in February 2021. These rapidly developed monoclonal antibodies have proven effective in reducing viral load and improving patient outcomes. The Fc region was modified to enhance stability. | Antibody | 7KMG, 7C01 | [324] |
Tixagevimab and Cilgavimab | SARS-CoV-2 | This combination, targeting SARS-CoV-2, received EUA for COVID-19 prevention and treatment and includes engineered Fc domains to reduce adverse effects. | Antibody | 8D8Q, 7L7E | [325] |
Sotrovimab | SARS-CoV-2 | B-cells from a SARS-CoV-infected individual, with an Fc domain modification to extend half-life, received FDA EUA in 2021 for treating mild-to-moderate COVID-19. | Antibody | - | [326] |
Spike protein Epitope-scaffolds a | SARS-CoV-2 | This study introduces a novel vaccine design strategy targeting conserved regions of the SARS-CoV-2 spike protein, bypassing the mutagenic receptor-binding domain. Using epitope grafting, stable immunogens mimicking these regions‘ surface features were engineered. Immunogenicity assessments in murine models showed promising results, and the designed epitope-scaffolds demonstrated potential diagnostic utility. | Nanoparticle Vaccine | - | [327] |
VHH60 | SARS-CoV-2 | Derived from the FDA-approved nanobody caplacizumab, this neutralizing nanobody binds the receptor-binding domain of the SARS-CoV-2 spike protein with high affinity (2.56 nM). It has shown significant efficacy in inhibiting virus infection in vitro and in vivo, making it a strong candidate for further clinical investigation against COVID-19. | Nanobody | - | [328] |
Family | Priority Pathogens | Virus | Viral Protein | PDB ID |
---|---|---|---|---|
Arenaviridae | Mammarenavirus lassaense | Lassa virus | Glycoprotein Complex (GPC) | 8TYE |
Nucleoprotein | 3MWP | |||
matrix protein Z | 5I72 | |||
spike complex | 7PVD | |||
L protein | 7OJJ | |||
Mammarenavirus juninense | Junin virus | GP1 glycoprotein | 5NUZ | |
Nucleoprotein | 4K7E | |||
L protein | 7EJU | |||
Z protein | 7EJU | |||
Mammarenavirus lujoense | Lujo Virus | spike complex | 8P4T | |
GP1 domain | 6GH8 | |||
Mamastrovirus virginiaense | Astrovirus | capsid spike | 7RK2 | |
Coronaviridae | Subgenus Merbecovirus | MERS | Spike Protein | 8SAK |
Fusion core | 4MOD | |||
Papain-like Potease | 4P16 | |||
3CL Protease | 4WMD | |||
nsP1 | 8T4S | |||
nsp5 protease | 4YLU | |||
nsP10 | 5YN5 | |||
nsP13 | 5WWP | |||
nsP16 | 5YN5 | |||
Nucleocapsid N-terminal Domain (NTD) | 4UD1 | |||
Nucleocapsid C-terminal Dmain | 7DYD | |||
Subgenus Sarbecovirus | SARS-CoV-2 | Spike Protein | 6M0J | |
Envelope Protein | 8U1T | |||
Membrane protein | 8CTK | |||
Nucleocapsid N-terminal Domain (NTD) | 7ACT | |||
Nucleocapsid C-terminal Dmain | 7O05 | |||
nsP1 | 7K3N | |||
nsP2 | 7MSX | |||
nsP3 (papain-like Protease) | 6W9C | |||
nsP5 (Main protease) | 6y2e | |||
nsP7 | 7JLT | |||
nsP8 | 7JLT | |||
nsP9 | 6WXD | |||
nsP10 | 5YN5 | |||
nsP12 | 6NUR | |||
nsp13 | 6ZSL | |||
nsp14 | 5C8S | |||
nsp15 | 6VWW | |||
nsp16 | 5YN5 | |||
Flaviviridae | Orthoflavivirus zikaense | Zika Virus | Envelope Protein | 5JHM, |
Membrane Protein | 7KCR | |||
NS5 Methyltransferase | 5GP1 | |||
Orthoflavivirus denguei | Dengue Virus | Envelope Protein | 1K4R, 7BUD | |
Membrane Protein | 7BUD | |||
NS3 protein | 5YVW | |||
NS2B/NS3 Protease | 2FOM | |||
NS5 | 8T12 | |||
Orthoflavivirus encephalitidis | Japanese encephalitis virus | Envelope Protein | 3P54 | |
Capsid | 5OW2 | |||
Membrane Protein | 5WSN | |||
Nsp1 CTD | 5O36 | |||
NS5 | 4K6M | |||
Orthohantavirus sinnombreense | Sin Nombre virus | Envelope Protein (Gc) | 7FGF | |
Envelope Protein (Gn) | 8AHN | |||
Nucleocapsid | 2IC9 | |||
Orthomyxoviridae | Alphainfluenzavirus Influenzae H1 | Influenza A Virus | Hemagglutinin H1 | 6CHX |
Hemagglutinin H5 | 5Z88 | |||
Neuraminidase | 4HZY | |||
RNA Polymerase | 6QPG | |||
Paramyxoviridae | Henipavirus nipahense | Nipah Virus | Fusion Core | 1WP7 |
Glycoprotein | 2VSM | |||
Matrix Protein | 7SKT | |||
Nucleoprotein | 4CO6 | |||
Phosphoprotein | 7PNO | |||
Polymerase | 9IR3 | |||
Poxviridae | Orthopoxvirus variola | Variola virus | Phosphoprotein | 6EB9 |
L1 protein | 1YPY | |||
Topoisomerase | 3IGC | |||
Orthopoxvirus vaccinia | Vaccinia Virus | DNA-dependent RNA polymerase complex | 6RFL | |
virulence factor F1L | 5AJJ | |||
Orthopoxvirus monkeypox | Monkeypox Virus | H3 envelope protein | 5EJ0 | |
methyltransferase VP39 | 8B07 | |||
Togaviridae | Alphavirus chikungunya | Chikungunya virus | E1 and E2 Envelope Glycoproteins | 2XFB |
Capsid Protein | 5H23 | |||
nsP2 Protease | 4ZTB | |||
nsP3 | 4TU0 | |||
nsP4 | 7VB4 | |||
Alphavirus venezuelan | Venezuelan Equine Encephalitis virus (VEEV) | Envelope Glycoprotein | 7SFV | |
nsP2 Protease | 5EZQ |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Handa, T.; Saha, A.; Narayanan, A.; Ronzier, E.; Kumar, P.; Singla, J.; Tomar, S. Structural Virology: The Key Determinants in Development of Antiviral Therapeutics. Viruses 2025, 17, 417. https://doi.org/10.3390/v17030417
Handa T, Saha A, Narayanan A, Ronzier E, Kumar P, Singla J, Tomar S. Structural Virology: The Key Determinants in Development of Antiviral Therapeutics. Viruses. 2025; 17(3):417. https://doi.org/10.3390/v17030417
Chicago/Turabian StyleHanda, Tanuj, Ankita Saha, Aarthi Narayanan, Elsa Ronzier, Pravindra Kumar, Jitin Singla, and Shailly Tomar. 2025. "Structural Virology: The Key Determinants in Development of Antiviral Therapeutics" Viruses 17, no. 3: 417. https://doi.org/10.3390/v17030417
APA StyleHanda, T., Saha, A., Narayanan, A., Ronzier, E., Kumar, P., Singla, J., & Tomar, S. (2025). Structural Virology: The Key Determinants in Development of Antiviral Therapeutics. Viruses, 17(3), 417. https://doi.org/10.3390/v17030417