The HIV-1 Gag proteins are synthesized as a polyprotein precursor, Pr55Gag, that is cleaved by protease (PR) during virus release from the infected cell. PR-mediated Pr55Gag processing follows a sequence of events that is kinetically controlled by the rate of processing at individual cleavage sites. 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'-dimethyl-succinyl) betulinic acid (PA-457 or bevirimat) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag processing pathway. We have performed initial characterization of the mechanism of action of PA-457 and have isolated and characterized a number of PA-457-resistant HIV-1 variants. In ongoing and future studies, we will fully define the mechanism of action of PA-457 and in collaboration with Panacos will develop second-generation maturation inhibitors that may be active against both wild-type and PA-457-resistant HIV-1 isolates. [Corresponds to Freed Project 4 in the April 2007 site visit report of the HIV Drug Resistance Program]

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010778-02
Application #
7733216
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2008
Total Cost
$297,129
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
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
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; 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 (2009) Anti-HIV-1 therapeutics: from FDA-approved drugs to hypothetical future targets. Mol Interv 9:70-4
Zhang, Hongtao; Zhao, Qian; Bhattacharya, Shibani et al. (2008) A cell-penetrating helical peptide as a potential HIV-1 inhibitor. J Mol Biol 378:565-80
Adamson, Catherine S; Freed, Eric O (2007) Human immunodeficiency virus type 1 assembly, release, and maturation. Adv Pharmacol 55:347-87