The HIV-1 Gag proteins are synthesized as a polyprotein precursor, Pr55Gag, that is cleaved by the viral protease during virus release from the infected cell. Completion of the Gag processing cascade is essential for virus maturation and infectivity. In collaboration with Panacos Pharmaceuticals, we found that 3-0-(3'-3'-dimethylsuccinyl) betulinic acid (PA-457 or bevirimat) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag processing pathway, the conversion of capsid-SP1 (CA-SP1) intermediate to mature CA. We identified the target of this compound by selecting for and characterizing a panel of drug-resistant mutants. Furthermore, we have recently initiated studies on a structurally distinct compound discovered by Pfizer that also blocks CA-SP1 processing and have identified a partially overlapping panel of resistant mutants. Some of the resistant mutants are highly assembly defective in the absence of the inhibitor and display a striking degree of drug dependence. Efforts are underway to understand the mechanistic basis for maturation inhibitor binding and activity. We hypothesize that defining the structure of the maturation inhibitor binding site(s) will greatly facilitate the development of novel and more potent inhibitors;to this end, we are collaborating with structural biology labs. Finally, we are collaborating with Drs. A. Debnath and M. Summers to define compounds that block maturation by targeting CA. Finally, we are involved in studies aimed at developing derivatives of bevirimat that display greater potency and broader activity against polymorphic isolates of HIV-1. [Corresponds to Freed Project 3 in the October 2011 site visit report of the HIV Drug Resistance Program]

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010778-07
Application #
8763211
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$316,876
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Adamson, Catherine S; Sakalian, Michael; Salzwedel, Karl et al. (2010) Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1 maturation inhibitor bevirimat. Retrovirology 7:36
Checkley, Mary Ann; Luttge, Benjamin G; Soheilian, Ferri et al. (2010) The capsid-spacer peptide 1 Gag processing intermediate is a dominant-negative inhibitor of HIV-1 maturation. Virology 400:137-44
Waheed, Abdul A; Ono, Akira; Freed, Eric O (2009) Methods for the study of HIV-1 assembly. Methods Mol Biol 485:163-84
Adamson, Catherine S; Salzwedel, Karl; Freed, Eric O (2009) Virus maturation as a new HIV-1 therapeutic target. Expert Opin Ther Targets 13:895-908
Adamson, Catherine S; Freed, Eric O (2009) Anti-HIV-1 therapeutics: from FDA-approved drugs to hypothetical future targets. Mol Interv 9:70-4
Adamson, Catherine S; Waki, Kayoko; Ablan, Sherimay D et al. (2009) Impact of human immunodeficiency virus type 1 resistance to protease inhibitors on evolution of resistance to the maturation inhibitor bevirimat (PA-457). J Virol 83:4884-94
Adamson, Catherine S; Freed, Eric O (2008) Recent progress in antiretrovirals--lessons from resistance. Drug Discov Today 13:424-32