Madison A. Wilkins

Background: Human immunodeficiency virus (HIV) infects immune cells, ultimately resulting in a decrease in the number of CD4+ T-cells and systemic immune failure in infected individuals.¹ HIV type 1 (HIV-1) is the predominant form of the virus in the United States.² Currently, antiretroviral treatments for HIV-1 include reverse transcriptase inhibitors, protease inhibitors, and integrase strand inhibitors.³ However, patients are often required to take multiple pills at specific times throughout the day, leading to medication fatigue. Medication fatigue leads to poor long-term adherence to these treatment regimens, leading to the emergence of resistant strains of the virus and reduced treatment efficacy. This phenomenon has encouraged the exploration of a class of molecules which target the HIV-1 capsid hexamer and have potential for long-term subcutaneous dosing to improve treatment adherence in patients with HIV-1.^2,4

Objective: In this narrative review, we explored the commonalities and therapeutic potentials of a new class of drugs designed to target the HIV-1 capsid hexamer.

Search Methods: An online search in the PubMed database was conducted from 2020-2024 using the following keywords: “HIV-1”, “capsid inhibitor”, and “small molecule”.

Results: Studies indicate that recently developed capsid protein inhibitors (GS-CA1, GS-6207, and Q-c4) bind a highly conserved site on the capsid hexamer known as the interprotomer pocket.^5,6,7 This site is an effective drug target because viral mutants with non-conserved mutations at this site display no infectivity due to abnormal morphology of the capsid hexamer.⁸ It was found that capsid inhibitors display potential as treatment options for heavily treatment experienced individuals with HIV-1 because they remain effective against known viral mutants and produce mutants with reduced infectivity.^5,6 Finally, it was found that GS-CA1 displayed low hepatic clearance in primary human hepatocytes and showed sustained drug release at all subcutaneously administered doses without bursts or rapid release in rats and dogs.^6,9 These studies indicate that capsid inhibitors have potential for long-acting subcutaneous dosing.

Conclusions: Studies have found that molecules which bind the interprotomer pocket of the HIV-1 capsid hexamer display promise as treatment options for individuals with heavily treatment experienced HIV-1. Additionally, due to their superb pharmacokinetic properties, these small molecules have potential for long-acting subcutaneous dosing to reduce medication fatigue and improve treatment adherence in persons with HIV-1.

Works cited:

1. Dwivedi R, Prakash P, Kumbhar BV, Balasubramaniam M, Dash C. HIV-1 capsid and viral DNA integration. mBio. 2024;15(1):e00212-22. doi:10.1128/mbio.00212-22
2. Saag MS. HIV Infection — Screening, Diagnosis, and Treatment. New England Journal of Medicine. 2021;384(22):2131-2143. doi:10.1056/NEJMcp1915826
3. Giacomelli A, Pezzati L, Rusconi S. The crosstalk between antiretrovirals pharmacology and HIV drug resistance. Expert Review of Clinical Pharmacology. 2020/07/02 2020;13(7):739-760. doi:10.1080/17512433.2020.1782737
4. Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. Lenacapavir: a first-in-class HIV 1 capsid inhibitor. Current Opinion in HIV and AIDS. 2022;17(1):15-21. doi:10.1097/coh.0000000000000713
5. Yant SR, Mulato A, Hansen D, et al. A highly potent long-acting small-molecule HIV-1 capsid inhibitor with
   efficacy in a humanized mouse model. Nature Medicine. 2019/09/01 2019;25(9):1377-1384.
   doi:10.1038/s41591-019-0560-x
6. Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule.
   2020;584(7822):614-618. doi:10.1038/s41586-020-2443-1
7. Zhang X, Sun L, Meuser ME, et al. Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors. Eur J Med Chem. 2021;226:113848. doi:10.1016/j.ejmech.2021.113848
8. Kobayakawa T, Yokoyama M, Tsuji K, et al. Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins. Biomolecules. 2021;11(2):208. Published 2021 Feb 3. doi:10.3390/biom11020208
9. Subramanian R, Tang J, Zheng J, et al. Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent. Molecular Pharmaceutics. 2023/12/04 2023;20(12):6213-6225. doi:10.1021/acs.molpharmaceut.3c00626