3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

SMALL MOLECULE HIV ENTRY INHIBITORS TARGETING GP41

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. TuOa0201

Jiang S., Lu H., Liu S., Zhao Q., He Y., Debnath A.K.
New York Blood Center, New York, United States of America

INTRODUCTION: T-20 (brand name: Fuzeon), a peptidic HIV-1 entry inhibitor targeting gp41, has been licensed by the US FDA for treatment of HIV-1 infected individuals who fail to respond to the current anti-retrovirus drugs. But this peptidic drug lacks oral availability and is very expensive. Therefore, development of orally available and inexpensive small molecule HIV-1 entry inhibitors targeting gp41 is urgently needed.

METHODS: A combination of cell- and ELISA-based high throughput screening (HTS) assays was used to screen chemical libraries for HIV-1 entry inhibitors targeting gp41. Immunological and biophysical assays were applied to study the binding sites and characterize the active compounds and their mechanism of action of the active compounds identified.

RESULTS: A series of low molecule weight compounds that inhibited HIV-1 entry and the gp41 six-helix bundle formation were identified. These compounds have potent inhibitory activity against all primary HIV-1 isolates tested, including those with distinct genotypes (clades A to G, and group O) and biotypes (X4, R5 and X4/R5). They significantly block formation of the gp41 fusion-active core.

CONCLUSIONS: These potent small molecule anti-HIV-1 compounds may interact with the components in the gp41 heptad repeat regions and block formation of the fusogenic core of six-helix bundle, thereby inhibiting gp41-mediated membrane fusion. These compounds will be used as leads for development of novel anti-HIV drugs, small molecule HIV entry inhibitors targeting gp41.

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050724
Basic | TuOa0201 | Shibo Jiang
6.1 490 6.1 New antiretroviral targets and compounds

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