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Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. 2020
Stephanie M Bester, and
Guochao Wei, and
Haiyan Zhao, and
Daniel Adu-Ampratwum, and
Naseer Iqbal, and
Valentine V Courouble, and
Ashwanth C Francis, and
Arun S Annamalai, and
Parmit K Singh, and
Nikoloz Shkriabai, and
Peter Van Blerkom, and
James Morrison, and
Eric M Poeschla, and
Alan N Engelman, and
Gregory B Melikyan, and
Patrick R Griffin, and
James R Fuchs, and
Francisco J Asturias, and
Mamuka Kvaratskhelia
Division of Infectious Diseases, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA.
The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.
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