HIV-1 capsid plays multiple critical roles throughout the viral replication cycle and is a novel target for therapeutic intervention. Unlike the present standard of care for people with HIV (PWH), inhibition of capsid function entails the disruption of a nonenzymatic target reliant on various protein-protein interactions, posing a significant challenge for small molecule drug development. Here we describe lenacapavir, MW 968[JL1] , a novel first-in-class small molecule HIV capsid inhibitor with potent in vitro antiviral activity (MT-4/HIV-1IIIb EC50 = 105 pM). Due to its high potency, low metabolic clearance, and slow-release kinetics, lenacapavir represents a novel long-acting antiretroviral agent for the treatment and prevention of HIV infection. Subcutaneous administration of lenacapavir in humans led to a slow and sustained release with an apparent half-life of 8 to 12 weeks. In people with HIV, lenacapavir demonstrated potent antiviral activity with up to 2.3 log10 reduction in plasma HIV-1 RNA. In heavily treatment experienced and treatment naïve PWH, lenacapavir in combination with other antiretroviral agents led to high rates of virologic suppression. Two large phase 3 studies are ongoing to evaluate subcutaneous lenacapavir for prevention of HIV-1 infection. To date, lenacapavir has been well tolerated. Numerous design cycles over many years were undertaken to discover the complex structural elements affording lenacapavir’s picomolar potency and exceptional metabolic stability that are the bases of lenacapavir’s long-acting pharmacokinetics and antiretroviral activity making lenacapavir suitable for twice yearly subcutaneous dosing.

Lenacapavir, a first-in-class long acting HIV capsid inhibitor

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ACS Fall 2022

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