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Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure

Faysal, KM Rifat; Walsh, James C; Renner, Nadine; Márquez, Chantal L; Shah, Vaibhav B; Tuckwell, Andrew J; Christie, Michelle P; ... Böcking, Till; + view all (2024) Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure. Elife , 13 , Article e83605. 10.7554/eLife.83605. Green open access

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Abstract

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.

Type: Article
Title: Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.7554/eLife.83605
Publisher version: http://dx.doi.org/10.7554/elife.83605
Language: English
Additional information: © 2024, Faysal, Walsh et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: HIV-1, capsid, drug mechanism of action, infectious disease, microbiology, molecular biophysics, none, structural biology
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10187888
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