Lenacapavir (Sunlenca®) for the treatment of HIV-1

STRUCTURE: Lenacapavir (previously GS-6207, brand name Sunlenca®) is a small molecule that selectively targets the HIV-1 capsid protein (CA, p24), which is a structural component of the virus. This is the first FDA-approved drug in the class of capsid protein inhibitors for clinical use in heavily treatment-experienced patients with multidrug-resistant HIV-1 infection. It has a molecular formula of C39H31ClF10N7O5S2 and a molecular weight of 968.28 g/mol. MECHANISM OF ACTION: The mechanism of action of lenacapavir involves its ability to target the HIV-1 capsid protein, rather than viral enzymes, which most current HIV-1 drugs target. The HIV-1 capsid is a cone-shaped structure comprising ~ 250 capsid hexamers and 12 pentamers. The capsid surrounds the viral genetic material and is important for viral particle assembly. Lenacapavir is a small molecule that binds to a pocket between the HIV capsid hexamer subunits. It interferes with both the early and late stages of the HIV life cycle; however, unlike other antiretroviral therapies, lenacapavir does not directly interfere with reverse transcription. In the initial stages of its effects (step 1), lenacapavir impedes the nuclear import of viral cDNA due to interference with the binding site for host-derived factors required for nuclear import. This includes nucleoporin 153 (Nup153) and cleavage and polyadenylation specificity factor subunit 6 (CPSF6), which are required for nuclear entry. This results in less proviral DNA integration. Additionally, lenacapavir reinforces the lattice of HIV-1 capsid protein–protein distal intra- and interhexamer interactions through hydrophobic and electrostatic interactions. This leads to a dose-dependent acceleration of capsid protein monomer assembly producing deformed capsids, which lead to defective HIV with reduced infectivity. Given that lenacapavir does not principally target viral enzymes, it has been suggested to be more resilient to viral mutation. In clinical trials, ~10% of patients showed emergent resistance through capsid mutations at M66I, Q67H, K70N/R/S, or N74D. Lenacapavir (GS-6207 during development), brand name of Sunlenca® Capsid inhibitor: targets the HIV-1 capsid protein, preventing nuclear entry, viral intergration, and ultimately inhibiting viral replication. As a first-in-class agent, lenacapavir is a long-acting injectable therapy for both early and late stages of HIV-1 infection. Through bi-yearly oral and/or subcutaneous usage, lenacapavir effectively reduces viral load using less frequent dosages compared with other drugs. Specifically, it has been approved in heavily treatment-experienced patients with multidrug-resistant HIV-1 infection. Concomitant use of lenacapavir with strong inducers of cytochrome P450 3A4 (e.g., rifampin, phenytoin, carbamazepine, etc.) decrease the levels and effects of lenacapavir. Gilead Sciences, Inc. Generally well tolerated in clinical trials, with minimal adverse effects reported. Most common reported adverse effects include injection site reactions (62%), such as swelling (31%), pain (31%), and erythema (25%). Nausea (12%), constipation or diarrhea (11%), headache (8%), urinary tract infection (7%), fevers (7%), and cough (8%) are other main adverse effects. 2018–2020, Phase 1, NCT03739866 2019–2024, Phase 2, NCT04143594 (CALIBRATE) 2019–2025, Phase 2/3, NCT04150068 (CAPELLA) 2021–2023, Phase 1, NCT04811040 2021–2027, Phase 3, NCT04925752 2021–2027, Phase 3, NCT04994509 2021–2027, Phase 2, NCT05052996 2022–2028, Phase 2/3, NCT05502341 August 2022, EU approval of lenacapavir December 2022, FDA approval of lenacapavir 2023–2029, Phase 2, NCT05729568 Figures drawn with ChemDraw and BioRender (biorender.com). The authors acknowledge funding from: United Negro College Fund (UNCF)/Bristol-Myers Squibb (UNCF/BMS) E.E. Just Postgraduate Fellowship in Life Sciences Fellowship and Burroughs Wellcome Fund/ PDEP #1022376 (H.K.B.); Doris Duke Clinical Scientist Development Award grant 2021193, Burroughs Wellcome Fund grant 1021480, and K23 HL156759 (C.N.W.); UNCF/BMS E.E. Just Faculty Fund, Career Award at the Scientific Interface (CASI Award) from Burroughs Welcome Fund (BWF) ID # 1021868.01, BWF Ad-hoc Award, National Institutes of Health (NIH) Small Research Pilot Subaward to 5R25HL106365-12 from the NIH PRIDE Program, DK020593, Vanderbilt Diabetes and Research Training Center for Department of Medicine's Diabetes Research and Training Center (DRTC) Alzheimer’s Disease Pilot & Feasibility Program, CZI Science Diversity Leadership grant number 2022-253529 from the Chan Zuckerberg Initiative DAF, and an advised fund of Silicon Valley Community Foundation (A.H.J.). The funders had no role in the study design, data collection, analysis, decision to publish, or manuscript preparation. None declared by authors.