The HIV-1 Gag proteins are synthesized as a polyprotein precursor, Pr55Gag, that is cleaved by 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'-dimethylsuccinyl) betulinic acid (PA-457 or bevirimat) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag processing pathway. We played a central role in defining the mechanism of action of bevirimat and have isolated and characterized a number of resistant HIV 1 variants. We are also investigating the target and mechanism of action of a compound (PF-46396) developed by Pfizer that is structurally distinct from bevirimat but like bevirimat blocks CA-SP1 processing. In ongoing studies, we are evaluating the antiviral activity of compounds that disrupt HIV-1 maturation by binding to the capsid protein. This work is being done in collaboration with Drs. A. Debnath and M. Summers. [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
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010778-05
Application #
8349153
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$346,945
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Freed, Eric O (2016) Getting IN on Viral RNA Condensation and Virion Maturation. Cell 166:1082-3
Timilsina, Uddhav; Ghimire, Dibya; Timalsina, Bivek et al. (2016) Identification of potent maturation inhibitors against HIV-1 clade C. Sci Rep 6:27403
Tedbury, Philip R; Freed, Eric O (2015) HIV-1 gag: an emerging target for antiretroviral therapy. Curr Top Microbiol Immunol 389:171-201
Freed, Eric O (2015) HIV-1 assembly, release and maturation. Nat Rev Microbiol 13:484-96
Fontana, Juan; Keller, Paul W; Urano, Emiko et al. (2015) Identification of an HIV-1 Mutation in Spacer Peptide 1 That Stabilizes the Immature CA-SP1 Lattice. J Virol 90:972-8
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Keller, Paul W; Huang, Rick K; England, Matthew R et al. (2013) A two-pronged structural analysis of retroviral maturation indicates that core formation proceeds by a disassembly-reassembly pathway rather than a displacive transition. J Virol 87:13655-64
Zhang, Hongtao; Curreli, Francesca; Waheed, Abdul A et al. (2013) Dual-acting stapled peptides target both HIV-1 entry and assembly. Retrovirology 10:136
Waheed, Abdul A; Freed, Eric O (2012) HIV type 1 Gag as a target for antiviral therapy. AIDS Res Hum Retroviruses 28:54-75
Waki, Kayoko; Durell, Stewart R; Soheilian, Ferri et al. (2012) Structural and functional insights into the HIV-1 maturation inhibitor binding pocket. PLoS Pathog 8:e1002997

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