Lenacapavir (Sunlenca, GS-6207) is a groundbreaking HIV drug developed by Gilead Sciences as a component of long-acting antiretroviral therapy. This first-in-class capsid inhibitor was approved by the EC in August 2022 and by the FDA in December 2022. Displaying impressive results in clinical trials, Lenacapavir has demonstrated the capability to maintain antiviral activity for six months with a single subcutaneous injection. An intriguing question arises - how does Lenacapavir exert its potent and sustained effects against HIV? Recent structural biology studies have unveiled its unique mechanism of action, targeting the HIV capsid protein.

The HIV capsid protein (p24) forms the cone-shaped core of the virus and plays essential roles throughout all stages of the viral replication cycle. Unlike other antiretroviral drugs targeting the viral enzymes reverse transcriptase, protease, and integrase, Lenacapavir directly binds the capsid protein at a conserved pocket located between two adjoining subunits. This binding process disrupts multiple capsid functions essential for HIV infectivity.

Specifically, the bond formed by Lenacapavir rigidifies the capsid structure, which prevents the controlled disassembly necessary during viral entry into host immune cells.

It also interferes with capsid interactions with key host proteins Nup153 and CPSF6 that are involved in nuclear import and integration site selection of the HIV genome. Additionally, Lenacapavir appears to intervene in the capsid-dependent assembly and release of the virus.

Structural studies have precisely outlined how Lenacapavir sinks deep into the capsid pocket, establishing extensive contact with conserved hydrophobic and charged residues. This direct interaction triggers long-range effects, stabilizing intra- and inter-subunit capsid interactions, important for preserving the proper curved lattice architecture. By contrast, another investigational capsid inhibitor, PF74, binds the target in a more superficial manner and lacks the comprehensive stabilizing effects possessed by Lenacapavir.

Resistance mutations selected by Lenacapavir are exclusively mapped to capsid residues lining the inhibitor binding pocket. However, these mutations that diminish antiviral potency also impair viral infectivity, thereby presenting a high barrier to resistance.

In conclusion, Lenacapavir capitalizes on the unique structural features of the multifunctional HIV capsid protein to achieve robust, prolonged antiretroviral activity through a groundbreaking mechanism of action. Understanding how this premier capsid inhibitor interacts with the capsid at an atomic level provides valuable insights and guidance in the design of the next generation of long-lasting HIV therapies.

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