The gp41 subunit of the HIV-1 envelope glycoprotein plays a major role in the fusion of viral and target cell membranes, leading to the release of the viral genetic material into the cell and to initiation of infection. The extracellular region of gp41 contains two heptad repeat (HR) regions that consist of hydrophobic sequences with high alpha-helical propensity, located adjacent to the N-terminal fusion peptide and at the C-terminus of the gp41 ectodomain, respectively. Peptides derived from the and C-terminal HR regions of gp41 have potent inhibitory activity on the membrane fusion step of HIV-1 infection. Biophysical and crystallographic studies suggest that in the fusion-active status, both regions interact with each other to form a six-helix bundle, consisting of three N-terminal and three C-terminal helices packed in the reverse direction and representing the fusion-active gp41 core structure. A conserved hydrophobic deep cavity in the coiled coil of gp41 plays an important role in stabilizing the helical-hairpin structure of the gp41 core and in membrane fusion, suggesting an attractive target for development of anti-HIV-1 agents. We hypothesize that low molecular weight organic compounds that dock into the hydrophobic cavity or bind to other sites of the and C-terminal heptad repeat regions of gp41 may interfere with the formation of the six-helix bundle of the gp41 core and block HIV-1-mediated membrane fusion.
The specific aims of this project are: 1) to identify lead antiviral compounds targeted to the HIV-1 gp41 core; 2) to determine the specificity of the lead antiviral compounds interacting with constituents of the HIV-1 gp41 core; 3) to optimize the lead antiviral compounds for generating most active anti-HIV-1 agents. The long-term goal is to develop novel anti-HIV-1 drugs for chemotherapy of HIV-1 infection and AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046221-02
Application #
6374290
Study Section
Special Emphasis Panel (ZRG1-AARR-3 (01))
Program Officer
Litterst, Charles L
Project Start
2000-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$290,336
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
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Cai, Lifeng; Pan, Chungen; Xu, Liang et al. (2012) Interactions between different generation HIV-1 fusion inhibitors and the putative mechanism underlying the synergistic anti-HIV-1 effect resulting from their combination. FASEB J 26:1018-26
Liu, Zhonghua; Shan, Mei; Li, Li et al. (2011) In vitro selection and characterization of HIV-1 variants with increased resistance to sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem 286:3277-87
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Li, Lin; Tan, Suiyi; Lu, Hong et al. (2011) Combinations of 3-hydroxyphthalic anhydride-modified ovalbumin with antiretroviral drug-based microbicide candidates display synergistic and complementary effects against HIV-1 infection. J Acquir Immune Defic Syndr 56:384-92
Wang, Ji; Tong, Pei; Lu, Lu et al. (2011) HIV-1 gp41 core with exposed membrane-proximal external region inducing broad HIV-1 neutralizing antibodies. PLoS One 6:e18233
Pan, Chungen; Cai, Lifeng; Lu, Hong et al. (2011) A novel chimeric protein-based HIV-1 fusion inhibitor targeting gp41 glycoprotein with high potency and stability. J Biol Chem 286:28425-34
Yu, Xiaoling; Yuan, Lin; Huang, Yang et al. (2011) Susceptibility of HIV-1 subtypes B', CRF07_BC and CRF01_AE that are predominantly circulating in China to HIV-1 entry inhibitors. PLoS One 6:e17605
Jiang, Shibo; Tala, Srinivasa R; Lu, Hong et al. (2011) Design, synthesis, and biological activity of novel 5-((arylfuran/1H-pyrrol-2-yl)methylene)-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-4-ones as HIV-1 fusion inhibitors targeting gp41. J Med Chem 54:572-9
Qin, Bingjie; Jiang, Xingkai; Lu, Hong et al. (2010) Diarylaniline derivatives as a distinct class of HIV-1 non-nucleoside reverse transcriptase inhibitors. J Med Chem 53:4906-16

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