Small hydroxyethylene-based peptidomimetics inhibiting both HIV-1 and C. albicans aspartic proteases Original Research Article

We have extended a highly flexible method for rapidly assembling aspartic protease inhibitors to produce symmetric and asymmetric monohydroxyethylene peptidomimetics. This method is based on the prior synthesis of the central non-cleavable peptide-bond isostere [NH2–P1ψP1′–NH2; ψ=hydroxyethylene isostere, HNCH(Bz)CHOHCH2CH(Bz)NH], with the possibility of accurately controlling its stereochemistry (S,S,S or S,R,S), and subsequently adding appropriate flanking units, chosen from commercially available amino acids, aromatic carboxylic acids, or phenoxyacetic acid (Poa) derivatives. The method was used to make asymmetric inhibitors of general formula Kyn-Xaa-PheψPhe-dmPoa, (Kyn=kynurenic acid, Xaa=Val, Thr or d-thienylglycine, Mr=716–754) and symmetric inhibitors of formula xPoa-PheψPhe-xPoa (xPoa=Poa or dimethyl-, hydroxy-, formyl- or acetyl-Poa, Mr=553–609), with logPo/w values ranging from 4.1 to 7.6. Inhibition of HIV-PR did not depend on the stereochemistry of the hydroxyl group, while it depended markedly on the substituents present on the Poa residues, with dmPoa being preferred over Poa or its more hydrophilic derivatives. Conversely, inhibition of Candida albicans Sap2 was higher for the S,S,S epimers, and Poa or its hydrophilic derivatives were preferred over dmPoa.