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 t heir inhibitory activity against HIV-1 in MT4 cell assay (IC50(1) = 2. 7 mu M). (The numbering scheme for gp41 (e.g., gp41(553-590) for 1) ad apted 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, si multaneous truncations of both N- and C- termini of gp41(553-590) resu lted in a potent heptadecamer, 13, IC50 = 10.4 mu M. Coupling of a rac emic alpha-aminotetradecanoic acid (Atd) to gp41 fragments afforded di astereomeric conjugates, most of which were chromatographically separa ble. In this series, pentadecamer 27 had an IC50 of 8.9 mu M, while it s Atd diastereomer 28 was much less inhibitory. This finding is consis tent with relative inhibitory potencies of other Atd-containing diaste reomeric pairs and could reflect a chiral sense of Atd residue interac ting with the receptor. Compounds 13 and 27, which are practically equ ipotent to 1, represent minimalistic fragments of the leucine-zipper r egion of gp41 and constitute a basis for design of a second generation of gp41-based inhibitors. Circular dichroism studies suggested that c ompounds in this series are likely to inhibit HIV-1 replication by vir tue of their alpha-helical character. The observed structure-activity relationship supports impairment of viral gp41 as a possible mechanism of action of 1.