Structural and mechanistic bases for a potent HIV-1 capsid inhibitor.

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Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, Francis AC, Annamalai AS, Singh PK, Shkriabai N, Van Blerkom P, Morrison J, Poeschla EM, Engelman AN, Melikyan GB, Griffin PR, Fuchs JR, Asturias FJ, Kvaratskhelia M

Structural and mechanistic bases for a potent HIV-1 capsid inhibitor.

Science. 2020 Oct 16;370(6514):360-364. doi: 10.1126/science.abb4808.

PubMed ID

33060363 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drugs

Lenacapavir

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Lenacapavir	Gag-Pol polyprotein	Protein		Yes	Inhibitor	Details