Lenacapavir allosterically remodels the HIV-1 capsid

Science Advances 2026 Open access

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Authors: Nayara F. B. dos Santos, Jacob A. Lewis, Mason Hansen, Miguel J. B. Pereira, Devin E. Christensen, Wesley I. Sundquist, Barbie K. Ganser-Pornillos, Owen Pornillos
DOI: 10.1126/sciadv.aed8384
Cited by: 7
References: 46

Abstract

Lenacapavir (LEN) is a highly potent, long-acting HIV-1 capsid inhibitor that holds exceptional promise for pre-exposure prophylaxis. LEN causes the mature viral capsid to rupture and lose integrity, but the underlying mechanism has been unclear. Here, we show that LEN is an allosteric modulator of HIV-1 capsid structure that breaks the capsid's fullerene cone architecture in two steps: loss of high-curvature declinations occurs early, followed by failure of the capsid body. At the molecular level, LEN alters the non-covalent bonding interactions between capsid subunits and reduces local lattice curvature. LEN also alters the material properties of the capsid, by increasing brittleness. These results provide molecular rationales for how LEN remodels HIV-1 capsid structure and impairs the replication capacity of the virus.

Fields of Study & Subjects

HIV Research and Treatment Dendrimers and Hyperbranched Polymers HIV/AIDS drug development and treatment

Publication details

Journal / source
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Volume
12
Issue
36
Pages
eaed8384–eaed8384
Publication date
2 September 2026
Language
EN