HIV capsid is a tractable target for small molecule therapeutic intervention.

Abstract:

:Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Blair WS,Pickford C,Irving SL,Brown DG,Anderson M,Bazin R,Cao J,Ciaramella G,Isaacson J,Jackson L,Hunt R,Kjerrstrom A,Nieman JA,Patick AK,Perros M,Scott AD,Whitby K,Wu H,Butler SL

doi

10.1371/journal.ppat.1001220

subject

Has Abstract

pub_date

2010-12-09 00:00:00

pages

e1001220

issue

12

eissn

1553-7366

issn

1553-7374

journal_volume

6

pub_type

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