Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region

The HIV-1 gp41 envelope glycoprotein promotes fusion of the virus and cell membranes through the formation of a trimer-of-hairpins structure, in which the amino- and carboxyl-terminal regions of the gp41 ectodomain are brough t together. Synthetic peptides derived from these two regions (called N and C peptides, respectively) inhibit HIV-1 entry. In contrast to C peptides, which inhibit in the nanomolar range, N peptides are weak inhibitors with I C50 values in the micromolar range. To test the hypothesis that the weak in hibition of N peptides results from their tendency to aggregate, we have co nstructed chimeric variants of the N-peptide region of gp41 in which solubl e trimeric coiled coils are fused to portions of the gp41 N peptide. These molecules, which present the N peptide in a trimeric coiled-coil conformati on, are remarkably more potent inhibitors than the N peptides themselves an d likely target the carboxyl-terminal region of the gp41 ectodomain. The be st inhibitors described here inhibit HIV-1 entry at nanomolar concentration s.