Small hydroxyethylene-based peptidomimetics inhibiting both HIV-1 and C. albicans aspartic proteases.
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.
Tossi
Alessandro
A
Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, Via Giorgieri 1, I-34127 Trieste, Italy. tossi@bbcm.units.it
Benedetti
Fabio
F
Norbedo
Stefano
S
Skrbec
Damiano
D
Berti
Federico
F
Romeo
Domenico
D
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
D004791:Enzyme Inhibitors; D005030:Ethylenes; D017320:HIV Protease Inhibitors; D010455:Peptides; D011994:Recombinant Proteins; C067254:hydroxyethylene; D016282:Aspartic Acid Endopeptidases