title: Small hydroxyethylene-based peptidomimetics inhibiting both HIV-1 and C. albicans aspartic proteases.
abstract: 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 [NH(2)-P(1)psiP1'-NH(2); psi=hydroxyethylene isostere, HNCH(Bz)CHOHCH(2)CH(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-PhepsiPhe-dmPoa, (Kyn=kynurenic acid, Xaa=Val, Thr or D-thienylglycine, M(r)=716-754) and symmetric inhibitors of formula xPoa-PhepsiPhe-xPoa (xPoa=Poa or dimethyl-, hydroxy-, formyl- or acetyl-Poa, M(r)=553-609), with logP(o/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.
authors.affiliation: Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, Via Giorgieri 1, I-34127 Trieste, Italy. tossi@bbcm.units.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tossi
authors.forename: Fabio
authors.initials: F
authors.lastname: Benedetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Norbedo
authors.forename: Damiano
authors.initials: D
authors.lastname: Skrbec
authors.forename: Federico
authors.initials: F
authors.lastname: Berti
authors.forename: Domenico
authors.initials: D
authors.lastname: Romeo
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002176:Candida albicans / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005030:Ethylenes / Q000737:chemistry* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005030:Ethylenes; D017320:HIV Protease Inhibitors; D010455:Peptides; D011994:Recombinant Proteins; C067254:hydroxyethylene; D016282:Aspartic Acid Endopeptidases