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 Pathogjournal_title
PLoS pathogensauthors
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 SLdoi
10.1371/journal.ppat.1001220subject
Has Abstractpub_date
2010-12-09 00:00:00pages
e1001220issue
12eissn
1553-7366issn
1553-7374journal_volume
6pub_type
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