Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV‑1 Treatment and Pre-exposure Prophylaxis

The HIV capsid is essential to the virus lifecycle, making
it a
promising target for therapeutic intervention. In 2006, a screening
campaign was initiated to identify small molecules capable of disrupting
the protein–protein interactions required for self-assembly
of the 1500 capsid monomers that form the 37 MDa fullerene cone-shaped
capsid. Numerous compound design cycles over many years were undertaken
to discover the complex structural elements that together afford the
multistage HIV capsid inhibitor lenacapavir. Lenacapavir is the most
potent (HIV-1 EC50 = 105 pM) and longest-acting HIV antiviral
to date, with a unique twice-yearly dosing regimen. Clinically, lenacapavir
has demonstrated robust efficacy for both HIV-1 treatment and prevention,
and, remarkably, achieved 100% protection in women for the first time.
These findings represent a significant advancement in treatment and
prevention of HIV-1 infection, offering the potential to profoundly
impact the global course of the HIV epidemic.