Therapeutic Targets in the Virological Mechanism and in the Hyperinflammatory Response of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2)
Abstract
:1. Introduction
2. Materials and Methods
3. Fundamental Structural Proteins
4. Envelope Protein
5. Biochemical–Molecular Mechanism of HCoV Infection
- Endocytosis of viral particles.
- Early translation of the positive ribonucleic acid (RNA) of SARS-CoV-2 as if it were host cell mRNA with the synthesis of early (regulatory) proteins, including polyproteins and essential viral proteases.
- Proteolysis through a protease. The polyproteins (pp1a and pp1ab) are cleaved into 16 nonstructural effector proteins by 3CLpro and PLpro.
- Formation of the replication complex together with the RNA-dependent RNA polymerase (RdRp).
- Synthesis of negative single-stranded RNA from the positive single-stranded RNA template by RNA polymerase, with formation of the replicative complex. The negative single-stranded RNA is not released, remaining associated with the replicative complex.
- The replicative complex produces synthesis of positive single-stranded RNA, mRNA, and negative single-stranded RNA.
- Late translation of positive single-stranded RNA and mRNA, with late (structural) protein synthesis on the ribosomes of the rough endoplasmic reticulum.
- Formation of viral particles with assembly in the ERGI intermediate compartment (endoplasmic reticulum–Golgi apparatus).
- Release of viral particles by exocytosis.
6. Etiopathogenic Phases of COVID-19
7. Physiopathology of Edema in Pulmonary Alveoli and Possible Therapeutic Targets
- The Na+/K+ ATP-ase pump, which allows two K+ ions to enter intracellularly and three Na+ ions to exit the cell by active transport.
- The epithelial channel of Na+ ions sensitive to amiloride (ENaC) (amiloride-sensitive sodium channel), which allows the transport of Na+ by facilitated diffusion. They are distributed in organs such as the lung, large intestine, kidney, vascular endothelium, and placenta.
- Cystic fibrosis transmembrane conductance regulator (CFTR), which belongs to the ABC transporters and exerts its function through primary active transport.
8. Therapy in the Viral Response Phase
8.1. Inhibitors of Viral Particle Entry
8.1.1. TMPRSS2 Inhibitors
8.1.2. Arbidol
8.1.3. Antimalarials
8.1.4. Janus-Associated Kinase (JAK) Inhibitors
8.1.5. Oseltamivir
8.1.6. Monoclonal Antibodies (MAbs) Directed against a Viral Coat Protein
8.1.7. ACE2 Soluble Receptor
8.2. RdRp Inhibitors [58]
8.3. Protease Inhibitors (PIs)
8.4. Inhibitors of Intracellular Transport of Viral Structures
9. The Hyperinflammatory Response in Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) Infection
10. Therapy in the Hyperinflammatory Response Phase with Immunomodulators of the Immune Inflammatory Cascade
10.1. Glucocorticosteroids
10.2. Antimalarials
10.3. Janus Kinase Inhibitor (JAK 1 and 2)
10.4. Blockers of the IL-1-Mediated Inflammatory Response
10.4.1. Anakinra (Kineret®)
10.4.2. Canakinumab (Illaris®)
10.4.3. Rilonacept (Arcalyst®)
10.5. Blockers of the Inflammatory Response Mediated by IL-6
10.5.1. Tocilizumab (Actemra®/RoActemra®)
10.5.2. Sarilumab (Kevzara®)
10.5.3. Siltuximab (Sylvant®)
10.6. Colchicine
10.7. Interferons
10.8. Passive Immunity
10.8.1. Sera from Patients Recovered from COVID-19
10.8.2. Combined Immunoglobulin Preparations
10.8.3. mAbs Directed against Any SARS-CoV-2 Protein
10.9. Active Immunity
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
mAb | monoclonal antibody |
RNA | ribonucleic acid |
COVID-19 | coronavirus disease 2019 (coronavirus disease-2019) |
CQ | chloroquine |
ACE2 | angiotensin-converting enzyme type II |
ERGI | intermediate compartment endoplasmic reticulum–Golgi apparatus |
HCoV | human coronavirus |
HCQ | hydroxychloroquine |
IFN | interferon |
IL-1 | interleukin 1 (interleukin 1) |
IL-6 | interleukin 6 (interleukin 6) |
IMPα/β1 | importin alpha and beta-1 |
PI | protease inhibitor |
JAK | Janus kinase (Janus kinase) |
MERS-CoV | virus causing Middle East respiratory syndrome (Middle East respiratory syndrome coronavirus) |
NS3 | nonstructural protein 3 |
RdRp | RNA-polymerase-RNA-dependent |
RDV | remdesivir |
SARS-CoV-1 | severe acute respiratory syndrome coronavirus 1 (severe acute respiratory syndrome coronavirus 1) |
SARS-CoV-2 | severe acute respiratory syndrome coronavirus 2 (severe acute respiratory syndrome coronavirus 2) |
TMPRSS2 | transmembrane protease, serine 2 |
HCV | hepatitis C virus |
HIV | human immunodeficiency virus |
RSV | respiratory syncytial virus |
References
- Novel Coronavirus (2019-nCoV) Situation Reports. Available online: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports (accessed on 23 January 2020).
- Haagmans, B.L.; Osterhaus, A.D. Coronaviruses and their therapy. Antivir. Res. 2006, 71, 397–403. [Google Scholar] [CrossRef] [PubMed]
- Paules, C.I.; Marston, H.D.; Fauci, A.S. Coronavirus Infections—More Than Just the Common Cold. JAMA 2020, 323, 707–708. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Masters, P.S. The Molecular Biology of Coronaviruses. Adv. Virus Res. 2006, 66, 193–292. [Google Scholar] [CrossRef] [PubMed]
- Siu, Y.L.; Teoh, K.T.; Lo, J.; Chan, C.M.; Kien, F.; Escriou, N.; Tsao, S.W.; Nicholls, J.M.; Altmeyer, R.; Peiris, J.S.M.; et al. The M, E, and N Structural Proteins of the Severe Acute Respiratory Syndrome Coronavirus Are Required for Efficient Assembly, Trafficking, and Release of Virus-Like Particles. J. Virol. 2008, 82, 11318–11330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kirchdoerfer, R.N.; Cottrell, C.A.; Wang, N.; Pallesen, J.; Yassine, H.M.; Turner, H.L.; Corbett, K.S.; Graham, B.S.; McLellan, J.S.; Ward, A.B. Pre-fusion structure of a human coronavirus spike protein. Nature 2016, 531, 118–121. [Google Scholar] [CrossRef] [Green Version]
- Song, H.C.; Seo, M.-Y.; Stadler, K.; Yoo, B.J.; Choo, Q.-L.; Coates, S.R.; Uematsu, Y.; Harada, T.; Greer, C.E.; Polo, J.M.; et al. Synthesis and Characterization of a Native, Oligomeric Form of Recombinant Severe Acute Respiratory Syndrome Coronavirus Spike Glycoprotein. J. Virol. 2004, 78, 10328–10335. [Google Scholar] [CrossRef] [Green Version]
- Iwata-Yoshikawa, N.; Okamura, T.; Shimizu, Y.; Hasegawa, H.; Takeda, M.; Nagata, N. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J. Virol. 2019, 93, e01815-18. [Google Scholar] [CrossRef] [Green Version]
- Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020, 181, 271–280.e8. [Google Scholar] [CrossRef]
- De Haan, C.A.; Rottier, P.J. Molecular interactions in the assembly of coronaviruses. Adv. Virus Res. 2005, 64, 165–230. [Google Scholar]
- Neuman, B.W.; Kiss, G.; Kunding, A.H.; Bhella, D.; Baksh, M.F.; Connelly, S.; Droese, B.; Klaus, J.P.; Makino, S.; Sawicki, S.G.; et al. A structural analysis of M protein in coronavirus assembly and morphology. J. Struct. Biol. 2011, 174, 11–22. [Google Scholar] [CrossRef]
- Venkatagopalan, P.; Daskalova, S.M.; Lopez, L.A.; Dolezal, K.A.; Hogue, B.G. Coronavirus envelope (E) protein remains at the site of assembly. Virology 2015, 478, 75–85. [Google Scholar] [CrossRef] [PubMed]
- Nieto-Torres, J.L.; DeDiego, M.L.; Álvarez, E.; Jiménez-Guardeño, J.M.; Regla-Nava, J.A.; Llorente, M.; Kremer, L.; Shuo, S.; Enjuanes, L. Subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein. Virology 2011, 415, 69–82. [Google Scholar] [CrossRef] [Green Version]
- DeDiego, M.L.; Álvarez, E.; Almazán, F.; Rejas, M.T.; Lamirande, E.; Roberts, A.; Shieh, W.-J.; Zaki, S.R.; Subbarao, K.; Enjuanes, L. A Severe Acute Respiratory Syndrome Coronavirus That Lacks the E Gene Is Attenuated In Vitro and In Vivo. J. Virol. 2007, 81, 1701–1713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kuo, L.; Masters, P.S. The Small Envelope Protein E Is Not Essential for Murine Coronavirus Replication. J. Virol. 2003, 77, 4597–4608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ortego, J.; Ceriani, J.E.; Patiño, C.; Plana, J.; Enjuanes, L. Absence of E protein arrests transmissible gastroenteritis coronavirus maturation in the secretory pathway. Virology 2007, 368, 296–308. [Google Scholar] [CrossRef] [Green Version]
- Curtis, K.M.; Yount, B.; Baric, R.S. Heterologous Gene Expression from Transmissible Gastroenteritis Virus Replicon Particles. J. Virol. 2002, 76, 10104–10110. [Google Scholar] [CrossRef] [Green Version]
- Ortego, J.; Escors, D.; Laude, H.; Enjuanes, L. Generation of a Replication-Competent, Propagation-Deficient Virus Vector Based on the Transmissible Gastroenteritis Coronavirus Genome. J. Virol. 2002, 76, 11518–11529. [Google Scholar] [CrossRef] [Green Version]
- Callaway, E. The race for coronavirus vaccines: A graphical guide. Nature 2020, 580, 576–577. [Google Scholar] [CrossRef]
- Le, T.T.; Andreadakis, Z.; Kumar, A.; Román, R.G.; Tollefsen, S.; Saville, M.; Mayhew, S. The COVID-19 vaccine development landscape. Nat. Rev. Drug Discov. 2020, 19, 305–306. [Google Scholar] [CrossRef]
- Kuo, L.; Hurst, K.R.; Masters, P.S. Exceptional Flexibility in the Sequence Requirements for Coronavirus Small Envelope Protein Function. J. Virol. 2007, 81, 2249–2262. [Google Scholar] [CrossRef] [Green Version]
- Arbely, E.; Khattari, Z.; Brotons, G.; Akkawi, M.; Salditt, T.; Arkin, I. A Highly Unusual Palindromic Transmembrane Helical Hairpin Formed by SARS Coronavirus E Protein. J. Mol. Biol. 2004, 341, 769–779. [Google Scholar] [CrossRef] [PubMed]
- Raamsman, M.J.B.; Locker, J.K.; De Hooge, A.; De Vries, A.A.F.; Griffiths, G.; Vennema, H.; Rottier, P.J.M. Characterization of the Coronavirus Mouse Hepatitis Virus Strain A59 Small Membrane Protein E. J. Virol. 2000, 74, 2333–2342. [Google Scholar] [CrossRef] [Green Version]
- Verdiá-Báguena, C.; Nieto-Torres, J.L.; Alcaraz, A.; DeDiego, M.L.; Torres, J.; Aguilella, V.M.; Enjuanes, L. Coronavirus E protein forms ion channels with functionally and structurally-involved membrane lipids. Virology 2012, 432, 485–494. [Google Scholar] [CrossRef] [Green Version]
- Nieto-Torres, J.L.; DeDiego, M.L.; Verdiá-Báguena, C.; Jimenez-Guardeño, J.M.; Regla-Nava, J.A.; Fernandez-Delgado, R.; Castaño-Rodriguez, C.; Alcaraz, A.; Torres, J.; Aguilella, V.M.; et al. Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis. PLoS Pathog. 2014, 10, e1004077. [Google Scholar] [CrossRef] [Green Version]
- Verdiá-Báguena, C.; Nieto-Torres, J.L.; Alcaraz, A.; DeDiego, M.L.; Enjuanes, L.; Aguilella, V.M. Analysis of SARS-CoV E protein ion channel activity by tuning the protein and lipid charge. Biochim. Biophys. Acta 2013, 1828, 2026–2031. [Google Scholar] [CrossRef] [Green Version]
- Corse, E.; Machamer, C.E. Infectious Bronchitis Virus E Protein Is Targeted to the Golgi Complex and Directs Release of Virus-Like Particles. J. Virol. 2000, 74, 4319–4326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Y.; Surya, W.; Claudine, S.; Torres, J. Structure of a Conserved Golgi Complex-targeting Signal in Coronavirus Envelope Proteins. J. Biol. Chem. 2014, 289, 12535–12549. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liao, Y.; Yuan, Q.; Torres, J.; Tam, J.P.; Liu, D. Biochemical and functional characterization of the membrane association and membrane permeabilizing activity of the severe acute respiratory syndrome coronavirus envelope protein. Virology 2006, 349, 264–275. [Google Scholar] [CrossRef] [PubMed]
- Torres, J.; Maheswari, U.; Parthasarathy, K.; Ng, L.; Liu, D.X.; Gong, X. Conductance and amantadine binding of a pore formed by a lysine-flanked transmembrane domain of SARS coronavirus envelope protein. Protein Sci. 2007, 16, 2065–2071. [Google Scholar] [CrossRef]
- Torres, J.; Wang, J.; Parthasarathy, K.; Liu, D.X. The Transmembrane Oligomers of Coronavirus Protein E. Biophys. J. 2005, 88, 1283–1290. [Google Scholar] [CrossRef] [Green Version]
- Parthasarathy, K.; Ng, L.; Lin, X.; Liu, D.X.; Pervushin, K.; Gong, X.; Torres, J. Structural Flexibility of the Pentameric SARS Coronavirus Envelope Protein Ion Channel. Biophys. J. 2008, 95, L39–L41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pervushin, K.; Tan, E.; Parthasarathy, K.; Lin, X.; Jiang, F.L.; Yu, D.; Vararattanavech, A.; Soong, T.W.; Liu, D.X.; Torres, J. Structure and Inhibition of the SARS Coronavirus Envelope Protein Ion Channel. PLoS Pathog. 2009, 5, e1000511. [Google Scholar] [CrossRef] [PubMed]
- Jimenez-Guardeño, J.M.; Nieto-Torres, J.L.; DeDiego, M.L.; Regla-Nava, J.A.; Fernandez-Delgado, R.; Castaño-Rodriguez, C.; Enjuanes, L. The PDZ-Binding Motif of Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Is a Determinant of Viral Pathogenesis. PLoS Pathog. 2014, 10, e1004320. [Google Scholar] [CrossRef] [Green Version]
- Castaño-Rodriguez, C.; Honrubia, J.M.; Gutiérrez-Álvarez, J.; DeDiego, M.L.; Nieto-Torres, J.L.; Jimenez-Guardeño, J.M.; Regla-Nava, J.A.; Fernandez-Delgado, R.; Verdia-Báguena, C.; Queralt-Martín, M.; et al. Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis. mBio 2018, 9, e02325-17. [Google Scholar] [CrossRef] [Green Version]
- Fehr, A.R.; Perlman, S. Coronaviruses: An overview of their replication and pathogenesis. In Coronaviruses; Methods in Molecular Biology; Humana Press: New York, NY, USA, 2015; Volume 1282, pp. 1–23. [Google Scholar]
- Liu, C.; Zhou, Q.; Li, Y.; Garner, L.V.; Watkins, S.P.; Carter, L.J.; Smoot, J.; Gregg, A.C.; Daniels, A.D.; Jervey, S.; et al. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci. 2020, 6, 315–331. [Google Scholar] [CrossRef] [PubMed]
- Aleem, A.; Akbar Samad, A.B.; Slenker, A.K. Emerging Variants of SARS-CoV-2 and Novel Therapeutics against Coronavirus (COVID-19). In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
- Siddiqi, H.K.; Mehra, M.R. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. J. Heart Lung Transplant. 2020, 39, 405–407. [Google Scholar] [CrossRef] [Green Version]
- Palma, A.G.; Kotsias, B.A.; Marino, G.I. Funciones de los canales iónicos CFTR y ENAC. Medicina 2014, 74, 133–139. [Google Scholar]
- Zhou, Y.; Vedantham, P.; Lu, K.; Agudelo, J.; Carrion, R., Jr.; Nunneley, J.W.; Barnard, D.; Pöhlmann, S.; McKerrow, J.H.; Renslo, A.R.; et al. Protease inhibitors targeting coronavirus and filovirus entry. Antivir. Res. 2015, 116, 76–84. [Google Scholar] [CrossRef]
- Su, S.-B.; Motoo, Y.; Iovanna, J.L.; Xie, M.-J.; Sawabu, N. Effect of Camostat Mesilate on the Expression of Pancreatitis-Associated Protein (PAP), p8, and Cytokines in Rat Spontaneous Chronic Pancreatitis. Pancreas 2001, 23, 134–140. [Google Scholar] [CrossRef]
- Yamamoto, M.; Matsuyama, S.; Li, X.; Takeda, M.; Kawaguchi, Y.; Inoue, J.-I.; Matsuda, Z. Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay. Antimicrob. Agents Chemother. 2016, 60, 6532–6539. [Google Scholar] [CrossRef] [Green Version]
- Kadam, R.U.; Wilson, I.A. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc. Natl. Acad. Sci. USA 2017, 114, 206–214. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fink, S.L.; Vojtech, L.; Wagoner, J.; Slivinski, N.S.J.; Jackson, K.J.; Wang, R.; Khadka, S.; Luthra, P.; Basler, C.F.; Polyak, S.J. The Antiviral Drug Arbidol Inhibits Zika Virus. Sci. Rep. 2018, 8, 8989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vankadari, N. Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein. Int. J. Antimicrob. Agents 2020, 56, 105998. [Google Scholar] [CrossRef] [PubMed]
- Chen, W.; Yao, M.; Fang, Z.; Lv, X.; Deng, M.; Wu, Z. A study on clinical effect of Arbidol combined with adjuvant therapy on COVID-19. J. Med. Virol. 2020, 92, 2702–2708. [Google Scholar] [CrossRef] [PubMed]
- Savarino, A.; Di Trani, L.; Donatelli, I.; Cauda, R.; Cassone, A. New insights into the antiviral effects of chloroquine. Lancet Infect. Dis. 2006, 6, 67–69. [Google Scholar] [CrossRef] [PubMed]
- Savarino, A.; Boelaert, J.R.; Cassone, A.; Majori, G.; Cauda, R. Effects of chloroquine on viral infections: An old drug against today’s diseases? Lancet Infect. Dis. 2003, 3, 722–727. [Google Scholar] [CrossRef]
- Taylor, P.C. Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology 2019, 58 (Suppl. S1), i17–i26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stebbing, J.; Krishnan, V.; De Bono, S.; Ottaviani, S.; Casalini, G.; Richardson, P.J.; Monteil, V.; Lauschke, V.M.; Mirazimi, A.; Youhanna, S.; et al. Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients. EMBO Mol. Med. 2020, 12, e12697. [Google Scholar] [CrossRef]
- Schwartz, D.M.; Kanno, Y.; Villarino, A.; Ward, M.; Gadina, M.; O’Shea, J.J. JAK inhibition as a therapeutic strtegy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 2017, 17, 78. [Google Scholar] [CrossRef] [Green Version]
- Askanase, A.D.; Khalili, L.; Buyon, J.P. Thoughts on COVID-19 and autoinmune diseases. Lupus Sci. Med. 2020, 7, e000396. [Google Scholar] [CrossRef] [Green Version]
- Jefferson, T.; Jones, M.A.; Doshi, P.; Del Mar, C.B.; Hama, R.; Thompson, M.J.; Spencer, E.A.; Onakpoya, I.J.; Mahtani, K.R.; Nunan, D.; et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database Syst. Rev. 2014, 2014, CD008965. [Google Scholar] [CrossRef] [Green Version]
- Chen, X.; Li, R.; Pan, Z.; Qian, C.; Yang, Y.; You, R.; Zhao, J.; Liu, P.; Gao, L.; Li, Z.; et al. Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor. Cell. Mol. Immunol. 2020, 17, 647–649. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Li, W.; Drabek, D.; Okba, N.M.A.; van Haperen, R.; Osterhaus, A.D.M.E.; van Kuppeveld, F.J.M.; Haagmans, B.L.; Grosveld, F.; Bosch, B.-J. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 2020, 11, 2251. [Google Scholar] [CrossRef] [PubMed]
- Monteil, V.; Kwon, H.; Prado, P.; Hagelkrüys, A.; Wimmer, R.A.; Stahl, M.; Leopoldi, A.; Garreta, E.; Del Pozo, C.H.; Prosper, F.; et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell 2020, 181, 905–913.e7. [Google Scholar] [CrossRef]
- Elfiky, A.A. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci. 2020, 248, 117477. [Google Scholar] [CrossRef] [PubMed]
- Furuta, Y.; Takahashi, K.; Kuno-Maekawa, M.; Sangawa, H.; Uehara, S.; Kozaki, K.; Nomura, N.; Egawa, H.; Shiraki, K. Mechanism of Action of T-705 against Influenza Virus. Antimicrob. Agents Chemother. 2005, 49, 981–986. [Google Scholar] [CrossRef] [Green Version]
- Furuta, Y.; Gowen, B.B.; Takahashi, K.; Shiraki, K.; Smee, D.F.; Barnard, D.L. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antivir. Res. 2013, 100, 446–454. [Google Scholar] [CrossRef] [Green Version]
- De Clercq, E. New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections. Chem.—Asian J. 2019, 14, 3962–3968. [Google Scholar] [CrossRef]
- Siegel, D.; Hui, H.C.; Doerffler, E.; Clarke, M.O.; Chun, K.; Zhang, L.; Neville, S.; Carra, E.; Lew, W.; Ross, B.; et al. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J. Med. Chem. 2017, 60, 1648–1661. [Google Scholar] [CrossRef] [Green Version]
- Sheahan, T.P.; Sims, A.C.; Graham, R.L.; Menachery, V.D.; Gralinski, L.E.; Case, J.B.; Leist, S.R.; Pyrc, K.; Feng, J.Y.; Trantcheva, I.; et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 2017, 9, eaal3653. [Google Scholar] [CrossRef] [Green Version]
- Grein, J.; Ohmagari, N.; Shin, D.; Diaz, G.; Asperges, E.; Castagna, A.; Feldt, T.; Green, G.; Green, M.L.; Lescure, F.X.; et al. Compassionate Use of Remdesivir for Patients with Severe COVID-19. N. Engl. J. Med. 2020, 382, 2327–2336. [Google Scholar] [CrossRef]
- Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020, 30, 269–271. [Google Scholar] [CrossRef] [PubMed]
- Arabi, Y.M.; Shalhoub, S.; Mandourah, Y.; Al-Hameed, F.; Al-Omari, A.; Al Qasim, E.; Jose, J.; Alraddadi, B.; Almotairi, A.; Al Khatib, K.; et al. Ribavirin and Interferon Therapy for Critically Ill Patients with Middle East Respiratory Syndrome: A Multicenter Observational Study. Clin. Infect. Dis. 2020, 70, 1837–1844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, Y.W.; Yiu, C.P.; Wong, K.Y. Prediction of the 2019-nCoV 3C-like protease (3CLpro) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. F1000Research 2020, 9, 129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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]
- Barragan, P.; Podzamczer, D. Lopinavir/ritonavir: A protease inhibitor for HIV-1 treatment. Expert Opin. Pharmacother. 2008, 9, 2363–2375. [Google Scholar] [CrossRef]
- Cao, B.; Wang, Y.; Wen, D.; Liu, W.; Wang, J.; Fan, G.; Ruan, L.; Song, B.; Cai, Y.; Wei, M.; et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe COVID-19. N. Engl. J. Med. 2020, 382, 1787–1799. [Google Scholar] [CrossRef]
- Sharun, K.; Dhama, K.; Patel, S.K.; Pathak, M.; Tiwari, R.; Singh, B.R.; Sah, R.; Bonilla-Aldana, D.K.; Rodriguez-Morales, A.J.; Leblebicioglu, H. Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19. Ann. Clin. Microbiol. Antimicrob. 2020, 19, 23. [Google Scholar] [CrossRef]
- Mastrangelo, E.; Pezzullo, M.; De Burghgraeve, T.; Kaptein, S.; Pastorino, B.; Dallmeier, K. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: New prospects for an old drug. J. Antimicrob. Chemother. 2012, 67, 1884–1894. [Google Scholar] [CrossRef] [Green Version]
- Tay, M.Y.F.; Fraser, J.E.; Chan, W.K.K.; Moreland, N.J.; Rathore, A.P.; Wang, C.; Vasudevan, S.G.; Jans, D.A. Nuclear localization of dengue virus (DENV) 1–4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antivir. Res. 2013, 99, 301–306. [Google Scholar] [CrossRef]
- Götz, V.; Magar, L.; Dornfeld, D.; Giese, S.; Pohlmann, A.; Höper, D. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci. Rep. 2016, 6, 23138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Caly, L.; Druce, J.D.; Catton, M.G.; Jans, D.A.; Wagstaff, K.M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir. Res. 2020, 178, 104787. [Google Scholar] [CrossRef] [PubMed]
- Franco, L.M.; Gadkari, M.; Howe, K.N.; Sun, J.; Kardava, L.; Kumar, P.; Kumari, S.; Hu, Z.; Fraser, I.D.; Moir, S.; et al. Immune regulation by glucocorticoids can be linked to cell type–dependent transcriptional responses. J. Exp. Med. 2019, 216, 384–406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Isidori, A.M.; Arnaldi, G.; Boscaro, M.; Falorni, A.; Giordano, C.; Giordano, R.; Pivonello, R.; Pofi, R.; Hasenmajer, V.; Venneri, M.A.; et al. COVID-19 infection and glucocorticoids: Update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency. J. Endocrinol. Investig. 2020, 43, 1141–1147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Van den Borne, B.E.; Dijkmans, B.A.; De Rooij, H.H.; Le Cessie, S.; Verweij, C.L. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J. Rheumatol. 1997, 24, 55–60. [Google Scholar] [PubMed]
- Chen, Z.; Hu, J.; Zhang, Z.; Jiang, S.; Han, S.; Yan, D.; Zhuang, R.; Hu, B.; Zhang, Z. Efficacy of Hydroxychloroquine in Patients with COVID-19: Results of a Randomized Clinical Trial. medRxiv 2020. [Google Scholar] [CrossRef] [Green Version]
- Gautret, P.; Lagier, J.C.; Parola, P.; Hoang, V.T.; Meddeb, L.; Mailhe, M.; Doudier, B.; Courjon, J.; Giordanengo, V.; Vieira, V.E.; et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents 2020, 56, 105949. [Google Scholar] [CrossRef]
- Million, M.; Lagier, J.-C.; Gautret, P.; Colson, P.; Fournier, P.-E.; Amrane, S.; Hocquart, M.; Mailhe, M.; Esteves-Vieira, V.; Doudier, B.; et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med. Infect. Dis. 2020, 35, 101738. [Google Scholar] [CrossRef]
- Lane, J.C.E.; Weaver, J.; Kostka, K.; Duarte-Salles, T.; Abrahao, M.T.F.; Alghoul, H.; Alser, O.; Alshammari, T.M.; Biedermann, P.; Burn, E.; et al. Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: A multinational, network cohort and self-controlled case series study. medRXiv 2020. [Google Scholar] [CrossRef] [Green Version]
- O’Shea, J.J.; Plenge, R. JAK and STAT Signaling Molecules in Immunoregulation and Immune-Mediated Disease. Immunity 2012, 36, 542–550. [Google Scholar] [CrossRef] [Green Version]
- Richardson, P.; Griffin, I.; Tucker, C.; Smith, D.; Oechsle, O.; Phelan, A.; Rawling, M.; Savory, E.; Stebbing, J. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020, 395, e30–e31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stebbing, J.; Phelan, A.; Griffin, I.; Tucker, C.; Oechsle, O.; Smith, D.; Richardson, P. COVID-19: Combining antiviral and anti-inflammatory treatments. Lancet Infect. Dis. 2020, 20, 400–402. [Google Scholar] [CrossRef] [PubMed]
- RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet 2022, 400, 359–368, Erratum in Lancet 2022, 400, 1102. [Google Scholar] [CrossRef]
- Boosman, R.J.; de Gooijer, C.J.; Groenland, S.L.; Burgers, J.A.; Baas, P.; van der Noort, V.; Beijnen, J.H.; Huitema, A.D.; Steeghs, N. Ritonavir-Boosted Exposure of Kinase Inhibitors: An Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib. Pharm. Res. 2022, 39, 669–676. [Google Scholar] [CrossRef] [PubMed]
- Cavalli, G.; De Luca, G.; Campochiaro, C.; Della-Torre, E.; Ripa, M.; Canetti, D.; Oltolini, C.; Castiglioni, B.; Din, C.T.; Boffini, N.; et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: A retrospective cohort study. Lancet Rheumatol. 2020, 2, e325–e331. [Google Scholar] [CrossRef] [PubMed]
- Dubois, E.A.; Rissmann, R.; Cohen, A.F. Rilonacept and canakinumab. Br. J. Clin. Pharmacol. 2011, 71, 639–641. [Google Scholar] [CrossRef] [Green Version]
- De Benedetti, F.; Gattorno, M.; Anton, J.; Ben-Chetrit, E.; Frenkel, J.; Hoffman, H.M.; Koné-Paut, I.; Lachmann, H.J.; Ozen, S.; Simon, A.; et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N. Engl. J. Med. 2018, 378, 1908–1919. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, X.; Han, M.; Li, T.; Sun, W.; Wang, D.; Fu, B.; Zhou, Y.; Zheng, X.; Yang, Y.; Li, X.; et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. Proc. Natl. Acad. Sci. USA 2020, 117, 10970–10975. [Google Scholar] [CrossRef]
- Raimondo, M.G.; Biggioggero, M.; Crotti, C.; Becciolini, A.; Favalli, E.G. Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. Drug Des. Dev. Ther. 2017, 11, 1593–1603. [Google Scholar] [CrossRef] [Green Version]
- Deisseroth, A.; Ko, C.-W.; Nie, L.; Zirkelbach, J.F.; Zhao, L.; Bullock, J.; Mehrotra, N.; Del Valle, P.; Saber, H.; Sheth, C.; et al. FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease. Clin. Cancer Res. 2015, 21, 950–954. [Google Scholar] [CrossRef] [Green Version]
- Bhattacharyya, B.; Panda, D.; Gupta, S.; Banerjee, M. Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin. Med. Res. Rev. 2008, 28, 155–183. [Google Scholar] [CrossRef] [PubMed]
- Massarotti, A.; Coluccia, A.; Silvestri, R.; Sorba, G.; Brancale, A. The Tubulin Colchicine Domain: A Molecular Modeling Perspective. ChemMedChem 2012, 7, 33–42. [Google Scholar] [CrossRef] [PubMed]
- Cronstein, B.N.; Molad, Y.; Reibman, J.; Balakhane, E.; Levin, R.I.; Weissmann, G. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J. Clin. Investig. 1995, 96, 994–1002. [Google Scholar] [CrossRef] [PubMed]
- Ferro, F.; Elefante, E.; Baldini, C.; Bartoloni, E.; Puxeddu, I.; Talarico, R.; Mosca, M.; Bombardieri, S. COVID-19: The new challenge for rheumatologists. First update. Clin. Exp. Rheumatol. 2020, 38, 175–180. [Google Scholar] [CrossRef]
- Parkin, J.; Cohen, B. An overview of the immune system. Lancet 2001, 357, 1777–1789. [Google Scholar] [CrossRef]
- Hensley, L.E.; Fritz, L.E.; Jahrling, P.B.; Karp, C.L.; Huggins, J.W.; Geisbert, T.W. Interferon-beta 1a and SARS coronavirus replication. Emerg. Infect. Dis. 2004, 10, 317–319. [Google Scholar] [CrossRef]
- Prencipe, G.; Bracaglia, C.; Caiello, I.; Pascarella, A.; Francalanci, P.; Pardeo, M.; Meneghel, A.; Martini, G.; Rossi, M.N.; Insalaco, A.; et al. The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis. PLoS ONE 2019, 14, e0226043. [Google Scholar] [CrossRef] [Green Version]
- Prokunina-Olsson, L.; Alphonse, N.; Dickenson, R.; Durbin, J.E.; Glenn, J.S.; Hartmann, R.; Kotenko, S.V.; Lazear, H.M.; O’Brien, T.R.; Odendall, C.; et al. COVID-19 and emerging viral infections: The case for interferon lambda. J. Exp. Med. 2020, 217, e20200653. [Google Scholar] [CrossRef] [Green Version]
- Duan, K.; Liu, B.; Li, C.; Zhang, H.; Yu, T.; Qu, J.; Zhou, M.; Chen, L.; Meng, S.; Hu, Y.; et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc. Natl. Acad. Sci. USA 2020, 117, 9490–9496. [Google Scholar] [CrossRef] [Green Version]
- Roback, J.D.; Guarner, J. Convalescent Plasma to Treat COVID-19: Possibilities and challenges. JAMA 2020, 323, 1561–1562. [Google Scholar] [CrossRef] [Green Version]
- Hung, I.F.N.; To, K.; Lee, C.-K.; Lee, K.-L.; Chan, K.K.C.; Yan, W.-W.; Liu, R.; Watt, C.-L.; Chan, W.-M.; Lai, K.-Y.; et al. Convalescent Plasma Treatment Reduced Mortality in Patients with Severe Pandemic Influenza A (H1N1) 2009 Virus Infection. Clin. Infect. Dis. 2011, 52, 447–456. [Google Scholar] [CrossRef] [PubMed]
- Dodd, R.Y. Emerging pathogens and their implications for the blood supply and transfusion transmitted infections. Br. J. Haematol. 2012, 159, 135–142. [Google Scholar] [CrossRef] [PubMed]
- Mair-Jenkins, J.; Saavedra-Campos, M.; Baillie, J.K.; Cleary, P.; Khaw, F.M.; Lim, W.S.; Makki, S.; Rooney, K.D.; Convalescent Plasma Study Group; Nguyen-Van-Tam, J.S.; et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. J. Infect. Dis. 2015, 211, 80–90. [Google Scholar] [CrossRef] [Green Version]
- The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998, 102 Pt 1, 531–537. [Google Scholar] [CrossRef]
- Westendorf, K.; Žentelis, S.; Wang, L.; Foster, D.; Vaillancourt, P.; Wiggin, M.; Lovett, E.; Van der Lee, R.; Hendle, J.; Pustilnik, A.; et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. bioRxiv 2022. Update in Cell Rep. 2022, 39, 110812. [Google Scholar] [CrossRef] [PubMed]
- Levin, M.J.; Ustianowski, A.; De Wit, S.; Launay, O.; Avila, M.; Templeton, A.; Yuan, Y.; Seegobin, S.; Ellery, A.; Levinson, D.J.; et al. Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of COVID-19. N. Engl. J. Med. 2022, 386, 2188–2200. [Google Scholar] [CrossRef]
- O’Neill, L.; Netea, M. BCG-induced trained immunity: Can it offer protection against COVID-19? Nat. Rev. Immunol. 2020, 20, 335–337. [Google Scholar] [CrossRef]
- Polack, F.P.; Thomas, S.J.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J.L.; Pérez Marc, G.; Moreira, E.D.; Zerbini, C.; et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 2020, 383, 2603–2615. [Google Scholar] [CrossRef]
- Baden, L.R.; El Sahly, H.M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S.A.; Rouphael, N.; Creech, C.B.; et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N. Engl. J. Med. 2021, 384, 403–416. [Google Scholar] [CrossRef]
- Sadoff, J.; Le Gars, M.; Shukarev, G.; Heerwegh, D.; Truyers, C.; de Groot, A.M.; Stoop, J.; Tete, S.; Van Damme, W.; Leroux-Roels, I.; et al. Interim Results of a Phase 1-2a Trial of Ad26.COV2.S COVID-19 Vaccine. N. Engl. J. Med. 2021, 384, 1824–1835. [Google Scholar] [CrossRef]
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Astasio-Picado, Á.; Zabala-Baños, M.d.C.; Jurado-Palomo, J. Therapeutic Targets in the Virological Mechanism and in the Hyperinflammatory Response of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2). Appl. Sci. 2023, 13, 4471. https://doi.org/10.3390/app13074471
Astasio-Picado Á, Zabala-Baños MdC, Jurado-Palomo J. Therapeutic Targets in the Virological Mechanism and in the Hyperinflammatory Response of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2). Applied Sciences. 2023; 13(7):4471. https://doi.org/10.3390/app13074471
Chicago/Turabian StyleAstasio-Picado, Álvaro, María del Carmen Zabala-Baños, and Jesús Jurado-Palomo. 2023. "Therapeutic Targets in the Virological Mechanism and in the Hyperinflammatory Response of Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2)" Applied Sciences 13, no. 7: 4471. https://doi.org/10.3390/app13074471