New Advances in Anti-HIV-1 Strategies Targeting the Assembly and Stability of Capsid Protein
Abstract
1. Introduction
2. New Advances Regarding the Structural Aspects of Novel HIV-1 Capsid Protein
3. Small Molecular Inhibitors for HIV-1 Capsid
3.1. PF74 and Its Derivatives
3.2. Lenacapavir and Its Derivatives
3.3. Other Molecules
4. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- HIV. Available online: https://www.who.int/zh/news-room/facts-in-pictures/detail/hiv-aids (accessed on 18 May 2025).
- Jones, J.E.; Sage, V.L.; Lakdawala, S.S. Viral and Host Heterogeneity and Their Effects on the Viral Life Cycle. Nat. Rev. Microbiol. 2020, 19, 272–282. [Google Scholar] [CrossRef] [PubMed]
- Ye, S.; Lu, C.; Qiu, Y.; Zheng, H.; Ge, X.; Wu, A.; Xia, Z.; Jiang, T.; Zhu, H.; Peng, Y. An Atlas of Human Viruses Provides New Insights into Diversity and Tissue Tropism of Human Viruses. Bioinformatics 2022, 38, 3087–3093. [Google Scholar] [CrossRef]
- He, M.; He, C.Q.; Ding, N.Z. Human Viruses: An Ever-Increasing List. Virology 2025, 604, 110445. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Caspar, D.L.D.; Klug, A. Physical Principles in the Construction of Regular Viruses. Cold Spring Harb. Symp. Quant. Biol. 1962, 27, 1–24. [Google Scholar] [CrossRef]
- Perlmutter, J.D.; Qiao, C.; Hagan, M.F. Viral Genome Structures Are Optimal for Capsid Assembly. eLife 2013, 2, e00632. [Google Scholar] [CrossRef] [PubMed]
- Yuan, S.; Wang, J.; Zhu, D.; Wang, N.; Gao, Q.; Chen, W.; Tang, H.; Wang, J.; Zhang, X.; Liu, H.; et al. Cryo-EM Structure of a Herpesvirus Capsid at 3.1 Å. Science 2018, 360, eaao7283. [Google Scholar] [CrossRef] [PubMed]
- Campbell, E.M.; Hope, T.J. HIV-1 Capsid: The Multifaceted Key Player in HIV-1 Infection. Nat. Rev. Microbiol. 2015, 13, 471–483. [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]
- Douglas, C.C.; Thomas, D.; Lanman, J.; Prevelige, P.E. Investigation of N-Terminal Domain Charged Residues on the Assembly and Stability of HIV-1 CA. Biochemistry 2004, 43, 10435–10441. [Google Scholar] [CrossRef]
- Mervis, R.J.; Ahmad, N.; Lillehoj, E.P.; Raum, M.G.; Salazar, F.H.; Chan, H.W.; Venkatesan, S. The Gag Gene Products of Human Immunodeficiency Virus Type 1: Alignment within the Gag Open Reading Frame, Identification of Posttranslational Modifications, and Evidence for Alternative Gag Precursors. J. Virol. 1988, 62, 3993–4002. [Google Scholar] [CrossRef] [PubMed]
- Ganser, B.K.; Li, S.; Klishko, V.Y.; Finch, J.T.; Sundquist, W.I. Assembly and Analysis of Conical Models for the HIV-1 Core. Science 1999, 283, 80–83. [Google Scholar] [CrossRef] [PubMed]
- Pornillos, O.; Ganser-Pornillos, B.K.; Kelly, B.N.; Hua, Y.; Whitby, F.G.; Stout, C.D.; Sundquist, W.I.; Hill, C.P.; Yeager, M. X-Ray Structures of the Hexameric Building Block of the HIV Capsid. Cell 2009, 137, 1282–1292. [Google Scholar] [CrossRef]
- Perilla, J.R.; Gronenborn, A.M. Molecular Architecture of the Retroviral Capsid. Trends Biochem. Sci. 2016, 41, 410–420. [Google Scholar] [CrossRef]
- Deshmukh, L.; Schwieters, C.D.; Grishaev, A.; Ghirlando, R.; Baber, J.L.; Clore, G.M. Structure and Dynamics of Full-Length HIV-1 Capsid Protein in Solution. J. Am. Chem. Soc. 2013, 135, 16133–16147. [Google Scholar] [CrossRef]
- Pornillos, O.; Ganser-Pornillos, B.K.; Yeager, M. Atomic-Level Modelling of the HIV Capsid. Nature 2011, 469, 424–427. [Google Scholar] [CrossRef]
- Gres, A.T.; Kirby, K.A.; KewalRamani, V.N.; Tanner, J.J.; Pornillos, O.; Sarafianos, S.G. X-Ray Crystal Structures of Native HIV-1 Capsid Protein Reveal Conformational Variability. Science 2015, 349, 99–103. [Google Scholar] [CrossRef] [PubMed]
- Zhao, G.; Perilla, J.R.; Yufenyuy, E.L.; Meng, X.; Chen, B.; Ning, J.; Ahn, J.; Gronenborn, A.M.; Schulten, K.; Aiken, C.; et al. Mature HIV-1 Capsid Structure by Cryo-Electron Microscopy and All-Atom Molecular Dynamics. Nature 2013, 497, 643–646. [Google Scholar] [CrossRef]
- Mattei, S.; Glass, B.; Hagen, W.J.H.; Kräusslich, H.G.; Briggs, J.A.G. The Structure and Flexibility of Conical HIV-1 Capsids Determined within Intact Virions. Science 2016, 354, 1434–1437. [Google Scholar] [CrossRef]
- Highland, C.M.; Tan, A.; Ricaña, C.L.; Briggs, J.A.G.; Dick, R.A. Structural Insights into HIV-1 Polyanion-Dependent Capsid Lattice Formation Revealed by Single Particle Cryo-EM. Proc. Natl. Acad. Sci. USA 2023, 120, e2220545120. [Google Scholar] [CrossRef]
- Gupta, M.; Pak, A.J.; Voth, G.A. Critical Mechanistic Features of HIV-1 Viral Capsid Assembly. Sci. Adv. 2023, 9, eadd7434. [Google Scholar] [CrossRef] [PubMed]
- Rihn, S.J.; Wilson, S.J.; Loman, N.J.; Alim, M.; Bakker, S.E.; Bhella, D.; Gifford, R.J.; Rixon, F.J.; Bieniasz, P.D. Extreme Genetic Fragility of the HIV-1 Capsid. PLoS Pathog. 2013, 9, e1003461. [Google Scholar] [CrossRef]
- Márquez, C.L.; Lau, D.; Walsh, J.; Shah, V.; McGuinness, C.; Wong, A.; Aggarwal, A.; Parker, M.W.; Jacques, D.A.; Turville, S.; et al. Kinetics of HIV-1 Capsid Uncoating Revealed by Single-Molecule Analysis. eLife 2018, 7, e34772. [Google Scholar] [CrossRef] [PubMed]
- Novikova, M.; Zhang, Y.; Freed, E.O.; Peng, K. Multiple Roles of HIV-1 Capsid during the Virus Replication Cycle. Virol. Sin. 2019, 34, 119–134. [Google Scholar] [CrossRef]
- Guedán, A.; Caroe, E.R.; Barr, G.C.R.; Bishop, K.N. The Role of Capsid in HIV-1 Nuclear Entry. Viruses 2021, 13, 1425. [Google Scholar] [CrossRef]
- Mamede, J.I.; Cianci, G.C.; Anderson, M.R.; Hope, T.J. Early Cytoplasmic Uncoating Is Associated with Infectivity of HIV-1. Proc. Natl. Acad. Sci. USA 2017, 114, E7169–E7178. [Google Scholar] [CrossRef]
- Francis, A.C.; Melikyan, G.B. Single HIV-1 Imaging Reveals Progression of Infection through CA-Dependent Steps of Docking at the Nuclear Pore, Uncoating, and Nuclear Transport. Cell Host Microbe 2018, 23, 536–548.e6. [Google Scholar] [CrossRef] [PubMed]
- Selyutina, A.; Persaud, M.; Lee, K.; KewalRamani, V.; Diaz-Griffero, F. Nuclear Import of the HIV-1 Core Precedes Reverse Transcription and Uncoating. Cell Rep. 2020, 32, 108201. [Google Scholar] [CrossRef]
- Burdick, R.C.; Li, C.; Munshi, M.; Rawson, J.M.O.; Nagashima, K.; Hu, W.S.; Pathak, V.K. HIV-1 Uncoats in the Nucleus near Sites of Integration. Proc. Natl. Acad. Sci. USA 2020, 117, 5486–5493. [Google Scholar] [CrossRef]
- Dharan, A.; Bachmann, N.; Talley, S.; Zwikelmaier, V.; Campbell, E.M. Nuclear Pore Blockade Reveals That HIV-1 Completes Reverse Transcription and Uncoating in the Nucleus. Nat. Microbiol. 2020, 5, 1088–1095. [Google Scholar] [CrossRef]
- Li, C.; Burdick, R.C.; Nagashima, K.; Hu, W.S.; Pathak, V.K. HIV-1 Cores Retain Their Integrity until Minutes before Uncoating in the Nucleus [Microbiology]. Proc. Natl. Acad. Sci. USA 2021, 118, e2019467118. [Google Scholar] [CrossRef] [PubMed]
- Gifford, L.B.; Melikyan, G.B. HIV-1 Capsid Uncoating Is a Multistep Process That Proceeds through Defect Formation Followed by Disassembly of the Capsid Lattice. ACS Nano 2024, 18, 2928–2947. [Google Scholar] [CrossRef]
- New Drug Therapy Approvals 2022. Available online: https://www.fda.gov/drugs/novel-drug-approvals-fda/new-drug-therapy-approvals-2022 (accessed on 18 May 2025).
- Yang, D.T.; Chong, L.T.; Gronenborn, A.M. Illuminating an Invisible State of the HIV-1 Capsid Protein CTD Dimer Using 19 F NMR and Weighted Ensemble Simulations. Proc. Natl. Acad. Sci. USA 2025, 122, e2420371122. [Google Scholar] [CrossRef]
- Sun, L.; Zhang, X.; Xu, S.; Huang, T.; Song, S.; Cherukupalli, S.; Zhan, P.; Liu, X. An Insight on Medicinal Aspects of Novel HIV-1 Capsid Protein Inhibitors. Eur. J. Med. Chem. 2021, 217, 113380. [Google Scholar] [CrossRef]
- Bhattacharya, A.; Alam, S.L.; Fricke, T.; Zadrozny, K.; Sedzicki, J.; Taylor, A.B.; Demeler, B.; Pornillos, O.; Ganser-Pornillos, B.K.; Diaz-Griffero, F.; et al. Structural Basis of HIV-1 Capsid Recognition by PF74 and CPSF6. Proc. Natl. Acad. Sci. USA 2014, 111, 18625–18630. [Google Scholar] [CrossRef]
- Peng, K.; Muranyi, W.; Glass, B.; Laketa, V.; Yant, S.R.; Tsai, L.; Cihlar, T.; Müller, B.; Kräusslich, H.G. Quantitative Microscopy of Functional HIV Post-Entry Complexes Reveals Association of Replication with the Viral Capsid. eLife 2014, 3, e04114. [Google Scholar] [CrossRef] [PubMed]
- Saito, A.; Ferhadian, D.; Sowd, G.A.; Serrao, E.; Shi, J.; Halambage, U.D.; Teng, S.; Soto, J.; Siddiqui, M.A.; Engelman, A.N.; et al. Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74. J. Virol. 2016, 90, 5808–5823. [Google Scholar] [CrossRef]
- Xu, S.; Sun, L.; Barnett, M.; Zhang, X.; Ding, D.; Gattu, A.; Shi, D.; Taka, J.R.H.; Shen, W.; Jiang, X.; et al. Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-One Scaffold as Potent HIV Capsid Modulators. J. Med. Chem. 2023, 66, 16303–16329. [Google Scholar] [CrossRef] [PubMed]
- Xu, S.; Wang, S.; Zhou, Y.; Foley, N.; Sun, L.; Walsham, L.; Tang, K.; Shi, D.; Shi, X.; Zhang, Z.; et al. “Pseudosubstrate Envelope”/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency. J. Med. Chem. 2024, 67, 19057–19076. [Google Scholar] [CrossRef]
- Sun, L.; Huang, T.; Dick, A.; Meuser, M.E.; Zalloum, W.A.; Chen, C.H.; Ding, X.; Gao, P.; Cocklin, S.; Lee, K.H.; et al. Design, Synthesis and Structure-Activity Relationships of 4-Phenyl-1H-1,2,3-Triazole Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Promising Antiviral Activities. Eur. J. Med. Chem. 2020, 190, 112085. [Google Scholar] [CrossRef]
- Link, J.O.; Rhee, M.S.; Tse, W.C.; Zheng, J.; Somoza, J.R.; Rowe, W.; Begley, R.; Chiu, A.; Mulato, A.; Hansen, D.; et al. Clinical Targeting of HIV Capsid Protein with a Long-Acting Small Molecule. Nature 2020, 584, 614–618. [Google Scholar] [CrossRef] [PubMed]
- Li, C.; Burdick, R.C.; Siddiqui, R.; Janaka, S.K.; Hsia, R.; Hu, W.S.; Pathak, V.K. Lenacapavir Disrupts HIV-1 Core Integrity While Stabilizing the Capsid Lattice. Proc. Natl. Acad. Sci. USA 2025, 122, e2420497122. [Google Scholar] [CrossRef] [PubMed]
- Gillis, E.P.; Parcella, K.; Bowsher, M.; Cook, J.H.; Iwuagwu, C.; Naidu, B.N.; Patel, M.; Peese, K.; Huang, H.; Valera, L.; et al. Potent Long-Acting Inhibitors Targeting the HIV-1 Capsid Based on a Versatile Quinazolin-4-One Scaffold. J. Med. Chem. 2023, 66, 1941–1954. [Google Scholar] [CrossRef]
- Wang, C.; Huang, H.; Mallon, K.; Valera, L.; Parcella, K.; Cockett, M.I.; Kadow, J.F.; Gillis, E.P.; Krystal, M.; Biology, R.A.F. Antiviral Properties of HIV-1 Capsid Inhibitor GSK878. Antimicrob. Agents Chemother. 2023, 67, e0169422. [Google Scholar] [CrossRef] [PubMed]
- Chia, T.; Nakamura, T.; Amano, M.; Takamune, N.; Matsuoka, M.; Nakata, H. A Small Molecule, ACAi-028, with Anti-HIV-1 Activity Targets a Novel Hydrophobic Pocket on HIV-1 Capsid. Antimicrob. Agents Chemother. 2021, 65, 10–1128. [Google Scholar] [CrossRef]
- Xu, J.P.; Francis, A.C.; Meuser, M.E.; Mankowski, M.; Ptak, R.G.; Rashad, A.A.; Melikyan, G.B.; Cocklin, S. Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action. J. Drug Des. Res. 2018, 5, 1070. [Google Scholar]
- Vernekar, S.K.V.; Sahani, R.L.; Casey, M.C.; Kankanala, J.; Wang, L.; Kirby, K.A.; Du, H.; Zhang, H.; Tedbury, P.R.; Xie, J.; et al. Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules. Viruses 2020, 12, 452. [Google Scholar] [CrossRef]
- Wang, L.; Casey, M.C.; Vernekar, S.K.V.; Do, H.T.; Sahani, R.L.; Kirby, K.A.; Du, H.; Hachiya, A.; Zhang, H.; Tedbury, P.R.; et al. Chemical Profiling of HIV-1 Capsid-Targeting Antiviral PF74. Eur. J. Med. Chem. 2020, 200, 112427. [Google Scholar] [CrossRef]
- Zhang, X.; Sun, L.; Xu, S.; Huang, T.; Zhao, F.; Ding, D.; Liu, C.; Jiang, X.; Tao, Y.; Kang, D.; et al. Design, Synthesis, and Mechanistic Study of 2-Piperazineone-Bearing Peptidomimetics as Novel HIV Capsid Modulators. RSC Med. Chem. 2023, 14, 1272–1295. [Google Scholar] [CrossRef]
- Sahani, R.L.; Diana-Rivero, R.; Vernekar, S.K.V.; Wang, L.; Du, H.; Zhang, H.; Castaner, A.E.; Casey, M.C.; Kirby, K.A.; Tedbury, P.R.; et al. Design, Synthesis and Characterization of HIV-1 CA-Targeting Small Molecules: Conformational Restriction of PF74. Viruses 2021, 13, 479. [Google Scholar] [CrossRef]
- Wang, L.; Casey, M.C.; Vernekar, S.K.V.; Sahani, R.L.; Kirby, K.A.; Du, H.; Zhang, H.; Tedbury, P.R.; Xie, J.; Sarafianos, S.G.; et al. Novel PF74-like Small Molecules Targeting the HIV-1 Capsid Protein: Balance of Potency and Metabolic Stability. Acta Pharm. Sin. B 2021, 11, 810–822. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Jiang, X.; Dick, A.; Prakash Sharma, P.; Chen, C.H.; Rathi, B.; Kang, D.; Wang, Z.; Ji, X.; Lee, K.H.; et al. Design, Synthesis, and Antiviral Activity of Phenylalanine Derivatives as HIV-1 Capsid Inhibitors. Bioorg. Med. Chem. 2021, 48, 116414. [Google Scholar] [CrossRef]
- Sun, L.; Dick, A.; Meuser, M.E.; Huang, T.; Zalloum, W.A.; Chen, C.H.; Cherukupalli, S.; Xu, S.; Ding, X.; Gao, P.; et al. Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities. J. Med. Chem. 2020, 63, 4790–4810. [Google Scholar] [CrossRef] [PubMed]
- Xu, S.; Sun, L.; Dick, A.; Zalloum, W.A.; Huang, T.; Meuser, M.E.; Zhang, X.; Tao, Y.; Cherukupalli, S.; Ding, D.; et al. Design, Synthesis, and Mechanistic Investigations of Phenylalanine Derivatives Containing a Benzothiazole Moiety as HIV-1 Capsid Inhibitors with Improved Metabolic Stability. Eur. J. Med. Chem. 2022, 227, 113903. [Google Scholar] [CrossRef]
- Wang, L.; Casey, M.C.; Vernekar, S.K.V.; Sahani, R.L.; Kankanala, J.; Kirby, K.A.; Du, H.; Hachiya, A.; Zhang, H.; Tedbury, P.R.; et al. Novel HIV-1 Capsid-Targeting Small Molecules of the PF74 Binding Site. Eur. J. Med. Chem. 2020, 204, 112626. [Google Scholar] [CrossRef]
- Selyutina, A.; Hu, P.; Miller, S.; Simons, L.M.; Yu, H.J.; Hultquist, J.F.; Lee, K.; KewalRamani, V.N.; Diaz-Griffero, F. GS-CA1 and Lenacapavir Stabilize the HIV-1 Core and Modulate the Core Interaction with Cellular Factors. iScience 2022, 25, 103593. [Google Scholar] [CrossRef]
- Bester, S.M.; Wei, G.; Zhao, H.; Adu-Ampratwum, D.; Iqbal, N.; Courouble, V.V.; Francis, A.C.; Annamalai, A.S.; Singh, P.K.; Shkriabai, N.; et al. Structural and Mechanistic Bases for a Potent HIV-1 Capsid Inhibitor. Science 2020, 370, 360–364. [Google Scholar] [CrossRef]
- Huang, S.W.; Briganti, L.; Annamalai, A.S.; Greenwood, J.; Shkriabai, N.; Haney, R.; Armstrong, M.L.; Wempe, M.F.; Singh, S.P.; Francis, A.C.; et al. The Primary Mechanism for Highly Potent Inhibition of HIV-1 Maturation by Lenacapavir. PLoS Pathog. 2025, 21, e1012862. [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]
- Ogbuagu, O.; Molina, J.M.; Chetchotisakd, P.; Ramgopal, M.N.; Sanchez, W.; Brunetta, J.; Castelli, F.; Crofoot, G.E.; Hung, C.C.; Ronot-Bregigeon, S.; et al. Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multidrug-Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial. Clin. Infect. Dis. 2025, 80, 566–574. [Google Scholar] [CrossRef]
- Bekker, L.G.; Das, M.; Karim, Q.A.; Ahmed, K.; Batting, J.; Brumskine, W.; Gill, K.; Harkoo, I.; Jaggernath, M.; Kigozi, G.; et al. Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. N. Engl. J. Med. 2024, 391, 1179–1192. [Google Scholar] [CrossRef]
- Blackwell, C.W.; Armstrong, F.; Castillo, H.L. Lenacapavir for HIV PrEP: Interim Phase III Clinical Data Evaluation. J. Nurse Pract. 2025, 21, 105360. [Google Scholar] [CrossRef]
- Jogiraju, V.; Pawar, P.; Yager, Y.; Ling, L.; Shen, G.; Chiu, A.; Hughes, E.; Palaparthy, R.; Carter, C.; Singh, R. Pharmacokinetics and Safety of Once-Yearly Lenacapavir: A Phase 1, Open-Label Study. Lancet 2025, 405, 1147–1154. [Google Scholar] [CrossRef]
- Hitchcock, A.M.; Kufel, W.D.; Dwyer, K.A.M.; Sidman, E.F. Lenacapavir: A Novel Injectable HIV-1 Capsid Inhibitor. Int. J. Antimicrob. Agents 2024, 63, 107009. [Google Scholar] [CrossRef] [PubMed]
- Bester, S.M.; Adu-Ampratwum, D.; Annamalai, A.S.; Wei, G.; Briganti, L.; Murphy, B.C.; Haney, R.; Fuchs, J.R.; Kvaratskhelia, M. Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor Lenacapavir. mBio 2022, 13, e01804-22. [Google Scholar] [CrossRef]
- Brigant, L.; Annamalai, A.S.; Bester, S.M.; Wei, G.; Andino-Moncada, J.R.; Singh, S.P.; Kleinpeter, A.B.; Tripathi, M.; Nguyen, B.; Radhakrishnan, R.; et al. Structural and Mechanistic Bases for Resistance of the M66I Capsid Variant to Lenacapavir. mBio 2025, 16, e03613-24. [Google Scholar] [CrossRef]
- Akther, T.; McFadden, W.M.; Zhang, H.; Kirby, K.A.; Sarafianos, S.G.; Wang, Z. Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein. Int. J. Mol. Sci. 2024, 25, 3734. [Google Scholar] [CrossRef] [PubMed]
- Akther, T.; McFadden, W.M.; Zhang, H.; Kirby, K.A.; Sarafianos, S.G.; Wang, Z. Quinazolinone-Based Subchemotypes for Targeting HIV-1 Capsid Protein: Design and Synthesis. Med. Chem. Res. 2024, 33, 2431–2447. [Google Scholar] [CrossRef] [PubMed]
- Kobayakawa, T.; Yokoyama, M.; Tsuji, K.; Fujino, M.; Kurakami, M.; Boku, S.; Nakayama, M.; Kaneko, M.; Ohashi, N.; Kotani, O.; et al. Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins. Biomolecules 2021, 11, 208. [Google Scholar] [CrossRef]
- Kobayakawa, T.; Yokoyama, M.; Tsuji, K.; Fujino, M.; Kurakami, M.; Onishi, T.; Boku, S.; Ishii, T.; Miura, Y.; Shinohara, K.; et al. Low-Molecular-Weight Anti-HIV-1 Agents Targeting HIV-1 Capsid Proteins. RSC Adv. 2023, 13, 2156–2167. [Google Scholar] [CrossRef]
- Kobayakawa, T.; Yokoyama, M.; Tsuji, K.; Boku, S.; Kurakami, M.; Fujino, M.; Ishii, T.; Miura, Y.; Nishimura, S.; Shinohara, K.; et al. Development of Small-Molecule Anti-HIV-1 Agents Targeting HIV-1 Capsid Proteins. Chem. Pharm. Bull. 2024, 72, 41–47. [Google Scholar] [CrossRef] [PubMed]
- Devadas, K.; Dhawan, S. Hemin Activation Ameliorates HIV-1 Infection via Heme Oxygenase-1 Induction. J. Immunol. 2006, 176, 4252–4257. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.W.; Xie, L.; Xu, X.S.; Li, Y.; Xu, X. A Broad-Spectrum Antiviral Molecule, Protoporphyrin IX, Acts as a Moderator of HIV-1 Capsid Assembly by Targeting the Capsid Hexamer. Microbiol. Spectr. 2023, 11, e0266322. [Google Scholar] [CrossRef]
- Zhang, D.W.; Xu, X.S.; Zhou, R.; Fu, Z. Modulation of HIV-1 Capsid Multimerization by Sennoside A and Sennoside B via Interaction with the NTD/CTD Interface in Capsid Hexamer. Front. Microbiol. 2023, 14, 1270258. [Google Scholar] [CrossRef]
- Artía, Z.; Guillon, C.; Robert, X.; Granzella, M.; Segovia, A.C.; Truong, H.H.; Álvarez, G.; Corvo, I.; Randall-Carlevaro, L. Integrating Different Approaches for the Identification of New Disruptors of HIV-1 Capsid Multimerization. Biochem. Biophys. Res. Commun. 2025, 763, 151572. [Google Scholar] [CrossRef] [PubMed]
- Thakkar, N.; Griesel, R.; Pierce, A.; Bainbridge, V.; Shepherd, B.; Angelis, K.; Tomlinson, A.; Gandhi, Y.; Brimhall, D.; Anderson, D.; et al. Clinical Pharmacokinetics and Safety of a New HIV-1 Capsid Inhibitor, VH4004280, After Oral Administration in Adults Without HIV. Infect. Dis. Ther. 2025, 14, 1313–1326. [Google Scholar] [CrossRef]
- Thakkar, N.; Griesel, R.; Pierce, A.; Bainbridge, V.; Shepherd, B.; Angelis, K.; Tomlinson, A.; Gandhi, Y.; Brimhall, D.; Spears, B.; et al. Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV. Infect. Dis. Ther. 2025, 14, 1011–1025. [Google Scholar] [CrossRef]
- Baeten, J.M. Lenacapavir for Human Immunodeficiency Virus (HIV) Prevention: A Commitment to Equitable Access and Partnership by Gilead Sciences. Clin. Infect. Dis. 2025, ciaf116. [Google Scholar] [CrossRef]
- Colson, A.E.; Crofoot, G.E.; Ruane, P.J.; Ramgopal, M.N.; Dretler, A.W.; Nahass, R.G.; Sinclair, G.I.; Berhe, M.; Shihadeh, F.; Liu, S.Y.; et al. 577. Week 48 Results of a Phase 2 Study Evaluating Once-Weekly Oral Islatravir Plus Lenacapavir. Open Forum Infect. Dis. 2025, 12, ofae631.015. [Google Scholar] [CrossRef]
- Mounzer, K.; Slim, J.; Ramgopal, M.; Hedgcock, M.; Bloch, M.; Santana, J.; Mendes, I.; Guo, Y.; Arora, P.; Montezuma-Rusca, J.M.; et al. Efficacy and Safety of Switching to Daily Bictegravir Plus Lenacapavir From a Complex Human Immunodeficiency Virus Treatment Regimen: A Randomized, Open-Label, Multicenter Phase 2 Study (ARTISTRY-1). Clin. Infect. Dis. 2024, 80, 881–888. [Google Scholar] [CrossRef]
- Gandhi, M.; Hill, L.; Grochowski, J.; Nelson, A.; Koss, C.A.; Mayorga-Munoz, F.; Oskarsson, J.; Shiels, M.; Avery, A.; Bamford, L.; et al. Case Series of People With HIV on the Long-Acting Combination of Lenacapavir and Cabotegravir: Call for a Trial. Open Forum Infect. Dis. 2024, 11, ofae125. [Google Scholar] [CrossRef] [PubMed]
- Wang, K.; Huang, Y.; Wang, Y.; You, Q.; Wang, L. Recent Advances from Computer-Aided Drug Design to Artificial Intelligence Drug Design. RSC Med. Chem. 2024, 15, 3978–4000. [Google Scholar] [CrossRef] [PubMed]
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Zhang, C.; Li, B.; Li, J.; Zhang, H.; Wu, Y. New Advances in Anti-HIV-1 Strategies Targeting the Assembly and Stability of Capsid Protein. Int. J. Mol. Sci. 2025, 26, 5819. https://doi.org/10.3390/ijms26125819
Zhang C, Li B, Li J, Zhang H, Wu Y. New Advances in Anti-HIV-1 Strategies Targeting the Assembly and Stability of Capsid Protein. International Journal of Molecular Sciences. 2025; 26(12):5819. https://doi.org/10.3390/ijms26125819
Chicago/Turabian StyleZhang, Chengfeng, Benteng Li, Jiamei Li, Haihong Zhang, and Yuqing Wu. 2025. "New Advances in Anti-HIV-1 Strategies Targeting the Assembly and Stability of Capsid Protein" International Journal of Molecular Sciences 26, no. 12: 5819. https://doi.org/10.3390/ijms26125819
APA StyleZhang, C., Li, B., Li, J., Zhang, H., & Wu, Y. (2025). New Advances in Anti-HIV-1 Strategies Targeting the Assembly and Stability of Capsid Protein. International Journal of Molecular Sciences, 26(12), 5819. https://doi.org/10.3390/ijms26125819