Synthesis and characterization of a library of peptidomimetics as potential inhibitors of HIV-gp41

HIV is treated by using a drug cocktail consisting of a reverse transcriptase and protease\ud inhibitor until drug resistance occurs, at such time Fuzeon, a 36 amino acid peptide fusion\ud inhibitor is administered. Fuzeon binds to and inhibits gp41, the fusion protein that\ud mediates host-viron fusion. Although Fuzeon is a highly effective treatment, its oral\ud unavailability and high cost reserves it for treatment of drug resistant forms of HIV.\ud Because of these limitations, small molecule alternatives for Fuzeon are actively being\ud sought. Our laboratory utilized computational docking experiments to design a series of\ud potential low molecular weight a-helical peptidomimetics for gp41 inhibition. Utilizing\ud protecting group chemistry, tert-butyl protected non-natural amino acids and an N-Boc\ud protected tryptophol nitrobenzoic acid scaffold were prepared as necessary intermediates.\ud Also prepared were naphthalene and 4-chlorophenyl nitrobenzoic acid scaffolds designed\ud by Boger and Gochin et al. Inhibitor analogues were produced from the protected amino\ud acids and the nitrobenzoic acid scaffold via solution phase peptide coupling\ud methodology. Deprotection was employed to provide the final inhibitor compounds after\ud purification by preparative HPLC. All molecules were characterized using 1H, 13C NMR\ud and LCMS. In this work, a library of a-helical peptidomimetics was prepared and their\ud structure activity relationship (SAR) was determined with the best compounds matching\ud previously published inhibitors