Inhibitors of human immunodeficiency virus type 1 derived from gp41 transmembrane protein: structure--activity studies.

We synthesized analogues of gp41 (553-590), 1, and evaluated them for their inhibitory activity against HIV-1 in MT4 cell assay (IC50(1) = 2.7 microM). (The numbering scheme for gp41 (e.g., gp41(553-590) for 1) adapted throughout the text is from ref 6.) Gradual truncation of either the N- or C-terminal end of gp41 (553-590) resulted in a substantial loss of inhibitory properties of resulting compounds. Unexpectedly, simultaneous truncations of both N- and C-termini of gp41(553-590) resulted in a potent heptadecamer, 13, IC50 = 10.4 microM. Coupling of a racemic alpha-aminotetradecanoic acid (Atd) to gp41 fragments afforded diastereomeric conjugates, most of which were chromatographically separable. In this series, pentadecamer 27 had an IC50 of 8.9 microM, while its Atd diastereomer 28 was much less inhibitory. This finding is consistent with relative inhibitory potencies of other Atd-containing diastereomeric pairs and could reflect a chiral sense of Atd residue interacting with the receptor. Compounds 13 and 27, which are practically equipotent to 1, represent minimalistic fragments of the leucine-zipper region of gp41 and constitute a basis for design of a second generation of gp41-based inhibitors. Circular dichroism studies suggested that compounds in this series are likely to inhibit HIV-1 replication by virtue of their alpha-helical character. The observed structure-activity relationship supports impairment of viral gp41 as a possible mechanism of action of 1.