Capsid (CA) protein is a major virion-constituent of all retroviruses including human immunodeficiency virus type 1 (HIV-1). It is essential for early and late phases in the viral replication cycle. Unlike the viral enzymes currently targeted by small molecule antiretroviral drugs, CA functions through protein-protein interactions. In the virion, Firstly, CA is released by PR-mediated precursor cleavage. Then, it self-assembles into a conical capsid composed of ~ 250 CA hexamers and 12 pentamers. Proper capsid formation and integrity are essential for virus infectivity. Upon infection of a new cell, controlled intracellular transport and disassembly of the viral capsid are regulated in part by interactions with host factors. Finally, support reverse transcription and proviral DNA integration.

Lenacapavir (GS-6207) is an HIV-1 Capsid Inhibitor for Infection Research

Lenacapavir (GS-6207), a small molecule, disrupts the functions of the HIV capsid protein. Firstly, Lenacapavir shows anti-HIV activity with an EC₅₀ value of 100 pM in MT-4 cells. Secondly, Lenacapavir displays a mean EC₅₀ value of 50 pM against 23 HIV-1 clinical isolates from different subtypes in peripheral blood mononuclear cells (PBMCs). Meanwhile, It exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that were tested. And it shows high synergy and no cross-resistance with approved antiretroviral drugs.

Furthermore, Lenacapavir has high potency, low in vivo systemic clearance, and slow-release kinetics from the subcutaneous injection site. In phase-1 clinical studies, Lenacapavir (subcutaneous, 450 mg, single) reduces the levels of plasma viral load. And it also shows sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein. And demonstrate the potential of Lenacapavir as a long-acting agent to treat or prevent infection with HIV.

In conclusion, Lenacapavir (GS-6207) is an HIV-1 capsid inhibitor for preventing HIV infection.

Reference：

[1] Singh K, et al. Front Microbiol. 2019;10:1227. Published 2019 Jun 20.

[2] Link JO, et al. Nature. 2020;584(7822):614-618.