15th International AIDS Conference Bangkok, Thailand - July 11-16, 2004

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. WeOrA1232)

Jiang S, Lu H, Liu S, Zhao Q, Debnath AK
New York Blood Center, New York, NY, United States

BACKGROUND: A peptidic HIV-1 fusion inhibitor targeting gp41, T-20 (Brand name: Fuzeon), was recently approved by the US FDA for treatment of HIV-1 infected individuals who fail to respond to the current anti-retrovirus drugs. But it has several disadvantages, including the lack of oral availability and high cost of production. Thus it is essential to develop small molecule non-peptidic HIV-1 fusion inhibitors that block the gp41 fusogenic core formation.

METHODS: We used high throughput screening (HTS) assays to screen chemical libraries for HIV-1 fusion inhibitors, and immunological and biophysical assays to characterize the small molecule anti-HIV-1 compounds and to study their mechanism of action.

RESULTS: We identified several low molecule weight compounds that inhibited HIV-1 replication and cell-cell fusion at low micromolar levels. These compounds did not block gp120-CD4 interaction, nor interact with the coreceptor CXCR4, but bound to the gp41 hydrophobic cavity and blocked the gp41 fusion-active core (six-helix bundle) formation. Conclusion These results support the hypotheses that a small molecule compounds, if binds a "hot-spot"± in a target protein, may block the protein-protein interaction. These small molecule HIV-1 fusion inhibitors identified here will be used as leads for development of a new class of anti-HIV drugs with a mechanism of action similar to T-20.

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WeOrA1232

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