1999 Scientific Retreat
Tim Strassmaier

Peptide-based Inhibitors of HIV-1
Mediated Membrane Fusion

The core of the human immunodeficiency virus (HIV) is encapsulated in a lipid membrane. In order for the viral core to gain access to a cell's interior-the first step in infection-the viral membrane must fuse with the cellular membrane. The viral glycoproteins gp12O and gp41 associated with the viral membrane are responsible for binding to specific cellular receptors and mediating fusion of the viral and cellular membranes. We have implemented a cell-cell fusion assay to measure the membrane fusion activity of HIV-1 gp12O/gp41. The cell-cell fusion assay was used to test the efficacy of hybrids between gp41 derived peptides and organic segments, identified from a combinatorial chemical library designed to yield small organic molecules capable of substituting for a portion of the gp41 peptide by binding to a particular cleft on gp41. Peptides, which bind to this cleft on gp41, are potent inhibitors of HIV membrane fusion. Small molecules that bind to this same cleft on gp41 could be lead compounds for the development of a new class of anti-HIV drugs. The peptide/organic hybrid inhibited HIV membrane fusion in the cell-cell fusion assay. The concentration of peptide/organic hybrid required to reduce the fusion activity by 50 percent, the EC50, was approximately tenfold lower than for the peptide alone. Further work will be required to identify organic compounds that can fully substitute for the peptide as inhibitors of HIV mediated membrane fusion.

 

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