Journal Article

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Wu, Hua, Scott, Andrew D., Hunt, Rachael, Ciaramella, Giuseppe, Patick, Amy K., Kjerrstrom, Anne, Jackson, Lynn, Pickford, Chris, Perros, Manos, Bazin, Richard, Brown, David G., Anderson, Marie, Isaacson, Jason, Cao, Joan, Blair, Wade S., Irving, Stephen L., Nieman, James A., Whitby, Kevin, Butler, Scott L.

2010

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / AIDS / Amino Acid Substitution / Anti-HIV Agents - chemistry / Anti-HIV Agents - pharmacology / Antiretroviral drugs / antiretroviral therapy / Antiviral activity / Antiviral agents / Binding Sites / Capsid Proteins - antagonists & inhibitors / Capsid Proteins - genetics / Capsids / Cell Line / Clinical isolates / Crystallography, X-Ray / Data processing / Disease resistance / Dosage and administration / Drug development / Drug resistance / Drug targeting / Drug therapy / HIV / HIV infection / HIV-1 - drug effects / HIV-2 - drug effects / Human immunodeficiency virus / Human immunodeficiency virus 1 / Human immunodeficiency virus 2 / Human Immunodeficiency Virus Proteins / Humans / Infection / Microbiology / Pathogens / Proteins / Replication / Structural proteins / Structure-Activity Relationship / Therapeutic applications / Uncoating / Virology/Antivirals, including Modes of Action and Resistance / Virology/Immunodeficiency Viruses / Virology/Viral and Gene Regulation / Virology/Virion Structure, Assembly, and Egress / Virus Replication - drug effects