HIV capsid inhibition explained

In the management of HIV/AIDS, HIV capsid inhibitors are antiretroviral medicines that target the capsid shell of the virus. This is in contrast to most current antiretroviral drugs used to treat HIV, which do not directly target the viral capsid.[1] These have also been termed "Capsid-targeting Antivirals", "Capsid Effectors", and "Capsid Assembly Modulators (CAMs)". Because of this, drugs that specifically inhibit the HIV capsid are being developed in order to reduce the replication of HIV, and treat infections that have become resistant to current antiretroviral therapies.[2]

History and background

HIV capsid

The mechanism of HIV infection involves the transport and integration of the viral genome into the DNA of the host cell. This process involves both viral and cellular proteins which reverse transcribe the viral RNA to double-stranded DNA, and incorporate the viral DNA into the host cell genome.[3]

The capsid surrounding the viral RNA, nucleocapsids, reverse transcriptase, and integrase plays a key role in the infection process. The capsid is composed of amino- and carboxy-terminal domains that form hexameric and pentameric rings. These rings assemble to form a cone-shaped structure surrounding the viral RNA and proteins.[4] Upon entering the cytoplasm of a host cell, the capsid goes through an unfolding process that releases the viral RNA and proteins into the cell.

The uncoating process is a highly ordered multistep process in which the capsid is weakened and most or all capsid proteins are removed from the shell. Upsetting this process can have downstream effects that significantly reduce the infectivity of the virus. Because of this, capsid uncoating is a favorable target for antiretroviral medicines.[5]

HIV treatment

Current drugs administered in the treatment of HIV do not target the capsid. Instead, patients are given a cocktail of reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry inhibitors.[6] These drugs have been successful on an epidemiologic and individual basis. With treatment, people infected by HIV are able to live long and healthy lives.[7]

As current treatments significantly reduce the mortality and morbidity of HIV, the disease is incurable but chronically manageable. Because patients typically need to take antiretroviral medications for the rest of their lives, long-term effects of HIV treatment are important to consider. Long term toxicological effects of antiretroviral treatments can sometimes cause secondary morbidities even when the viral count is low. Additionally, drug resistances can be acquired or transmitted due to suboptimal pharmokinetics or lack of patient adherence to treatment.[8]

Therapeutic applications

Lenacapavir

Lenacapavir is a capsid inhibitor developed by Gilead Sciences. It functions by binding to the hydrophobic pocket formed by two neighboring protein subunits in the capsid shell.[9] This bond stabilizes the capsid structure and inhibits the functional disassembly of the capsid in infected cells.

Lenacapavir was approved for medical use in the European Union in August 2022,[10] in Canada in November 2022,[11] [12] and in the United States in December 2022.[13] Lenacapavir is the first capsid inhibitor to be FDA-approved for treating HIV/AIDS.

Research

History

In 2003, the first compound to bind the HIV-1 capsid was reported and termed "CAP-1".[14] Since then, over 40 molecules have been reported to inhibit HIV-1 by binding capsid, with five distinct chemotypes described. The binding pocket for Lenacapavir was first described in 2009, with the small molecule PF-3450074 (PF74) developed by Pfizer.[15] PF74 was not developed clinically due to its fast metabolic breakdown and poor bioavailability, but its binding pocket has been well characterized and frequently targeted.

GS-CA1

GS-CA1 is an experimental small-molecule capsid inhibitor developed by Gilead Sciences. GS-CA1 and GS-6207 are analogues, with both molecules showing promising anti-HIV activity.

GS-CA1 functions by binding directly to the HIV capsid. This bonding disrupts the uncoating process which inhibits both the release of viral RNA and proteins into the cytoplasm, and also inhibits the production of new capsid shells within the cell.[16]

Ebselen

Ebselen was identified as a capsid inhibitor using a fluorescence assay on a library of pharmacological compounds. Ebselen covalently bonds to the C-terminal domain of the HIV-1 capsid, which inhibits the uncoating process. Ebselen shows anti-HIV activity in infected cell lines.

Peptides

Phage display was used to identify peptides that bind the HIV-1 capsid protein, and the most promising peptide inhibitor was the Capsid Assembly Inhibitor (CAI) peptide.[17] CAI prevented the formation of mature capsids, but its poor permeability in cells limited its use. Other peptide inhibitors have been reported,[18] as well as next generation inhibitors with increased stability, permeability, and antiviral activity.[19] These peptides interact at the C-terminal domain of the HIV-1 capsid, similar to Ebselen.

Uracil-based drugs

Uracil based scaffolds such as bispyrimidine dione and tetrapyrimidine dione derivatives have shown activity as HIV-1 p24 capsid inhibitors in an in vitro setting but need further exploration.[20]

See also

Notes and References

  1. Web site: FDA-Approved HIV Medicines NIH . 2023-05-25 . hivinfo.nih.gov . en.
  2. McFadden WM, Snyder AA, Kirby KA, Tedbury PR, Raj M, Wang Z, Sarafianos SG . Rotten to the core: antivirals targeting the HIV-1 capsid core . Retrovirology . 18 . 1 . 41 . December 2021 . 34937567 . 8693499 . 10.1186/s12977-021-00583-z . free .
  3. Isel C, Ehresmann C, Marquet R . Initiation of HIV Reverse Transcription . Viruses . 2 . 1 . 213–243 . January 2010 . 21994608 . 3185550 . 10.3390/v2010213 . free .
  4. Pornillos O, Ganser-Pornillos BK, Yeager M . Atomic-level modelling of the HIV capsid . Nature . 469 . 7330 . 424–427 . January 2011 . 21248851 . 3075868 . 10.1038/nature09640 . 2011Natur.469..424P .
  5. Ambrose Z, Aiken C . HIV-1 uncoating: connection to nuclear entry and regulation by host proteins . Virology . 454-455 . 371–379 . April 2014 . 24559861 . 3988234 . 10.1016/j.virol.2014.02.004 .
  6. Thenin-Houssier S, de Vera IM, Pedro-Rosa L, Brady A, Richard A, Konnick B, Opp S, Buffone C, Fuhrmann J, Kota S, Billack B, Pietka-Ottlik M, Tellinghuisen T, Choe H, Spicer T, Scampavia L, Diaz-Griffero F, Kojetin DJ, Valente ST . 6 . Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication . Antimicrobial Agents and Chemotherapy . 60 . 4 . 2195–2208 . April 2016 . 26810656 . 4808204 . 10.1128/AAC.02574-15 .
  7. Moreno S, López Aldeguer J, Arribas JR, Domingo P, Iribarren JA, Ribera E, Rivero A, Pulido F . 6 . The future of antiretroviral therapy: challenges and needs . The Journal of Antimicrobial Chemotherapy . 65 . 5 . 827–835 . May 2010 . 20228080 . 10.1093/jac/dkq061 . free .
  8. Taiwo B, Hicks C, Eron J . Unmet therapeutic needs in the new era of combination antiretroviral therapy for HIV-1 . The Journal of Antimicrobial Chemotherapy . 65 . 6 . 1100–1107 . June 2010 . 20348088 . 10.1093/jac/dkq096 . free .
  9. Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, Francis AC, Annamalai AS, Singh PK, Shkriabai N, Van Blerkom P, Morrison J, Poeschla EM, Engelman AN, Melikyan GB, Griffin PR, Fuchs JR, Asturias FJ, Kvaratskhelia M . 6 . Structural and mechanistic bases for a potent HIV-1 capsid inhibitor . Science . 370 . 6514 . 360–364 . October 2020 . 33060363 . 7831379 . 10.1126/science.abb4808 . 2020Sci...370..360B .
  10. Web site: Sunlenca EPAR . European Medicines Agency (EMA) . 22 June 2022 . 25 August 2022 . 26 August 2022 . https://web.archive.org/web/20220826024847/https://www.ema.europa.eu/en/medicines/human/EPAR/sunlenca . live .
  11. Web site: Sunlenca Product information (oral). . 25 April 2012 . 23 December 2022.
  12. Web site: Sunlenca Product information (subcutaneous) . . 25 April 2012 . 23 December 2022.
  13. FDA Approves New HIV Drug for Adults with Limited Treatment Options . U.S. Food and Drug Administration (FDA) . 22 December 2022 . 23 December 2022.
  14. Tang C, Loeliger E, Kinde I, Kyere S, Mayo K, Barklis E, Sun Y, Huang M, Summers MF . 6 . Antiviral inhibition of the HIV-1 capsid protein . Journal of Molecular Biology . 327 . 5 . 1013–1020 . April 2003 . 12662926 . 10.1016/S0022-2836(03)00289-4 .
  15. Blair WS, Pickford C, Irving SL, Brown DG, Anderson M, Bazin R, Cao J, Ciaramella G, Isaacson J, Jackson L, Hunt R, Kjerrstrom A, Nieman JA, Patick AK, Perros M, Scott AD, Whitby K, Wu H, Butler SL . 6 . HIV capsid is a tractable target for small molecule therapeutic intervention . PLOS Pathogens . 6 . 12 . e1001220 . December 2010 . 21170360 . 3000358 . 10.1371/journal.ppat.1001220 . Luban J . free .
  16. Yant SR, Mulato A, Hansen D, Tse WC, Niedziela-Majka A, Zhang JR, Stepan GJ, Jin D, Wong MH, Perreira JM, Singer E, Papalia GA, Hu EY, Zheng J, Lu B, Schroeder SD, Chou K, Ahmadyar S, Liclican A, Yu H, Novikov N, Paoli E, Gonik D, Ram RR, Hung M, McDougall WM, Brass AL, Sundquist WI, Cihlar T, Link JO . 6 . A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model . Nature Medicine . 25 . 9 . 1377–1384 . September 2019 . 31501601 . 7396128 . 10.1038/s41591-019-0560-x .
  17. Sticht J, Humbert M, Findlow S, Bodem J, Müller B, Dietrich U, Werner J, Kräusslich HG . 6 . A peptide inhibitor of HIV-1 assembly in vitro . Nature Structural & Molecular Biology . 12 . 8 . 671–677 . August 2005 . 16041387 . 10.1038/nsmb964 . 5953442 .
  18. Bocanegra R, Nevot M, Doménech R, López I, Abián O, Rodríguez-Huete A, Cavasotto CN, Velázquez-Campoy A, Gómez J, Martínez MÁ, Neira JL, Mateu MG . 6 . Rationally designed interfacial peptides are efficient in vitro inhibitors of HIV-1 capsid assembly with antiviral activity . PLOS ONE . 6 . 9 . e23877 . 2011-09-08 . 21931621 . 3169566 . 10.1371/journal.pone.0023877 . 2011PLoSO...623877B . free .
  19. Zhang H, Zhao Q, Bhattacharya S, Waheed AA, Tong X, Hong A, Heck S, Curreli F, Goger M, Cowburn D, Freed EO, Debnath AK . 6 . A cell-penetrating helical peptide as a potential HIV-1 inhibitor . Journal of Molecular Biology . 378 . 3 . 565–580 . May 2008 . 18374356 . 2695608 . 10.1016/j.jmb.2008.02.066 .
  20. Ramesh D, Mohanty AK, De A, Vijayakumar BG, Sethumadhavan A, Muthuvel SK, Mani M, Kannan T . 6 . Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies . RSC Advances . 12 . 27 . 17466–17480 . June 2022 . 35765450 . 9190787 . 10.1039/D2RA02450K . 2022RSCAd..1217466R .

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