Document Detail

Small hydroxyethylene-based peptidomimetics inhibiting both HIV-1 and C. albicans aspartic proteases.
MedLine Citation:
PMID:  14556787     Owner:  NLM     Status:  MEDLINE    
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.
Alessandro Tossi; Fabio Benedetti; Stefano Norbedo; Damiano Skrbec; Federico Berti; Domenico Romeo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  11     ISSN:  0968-0896     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-10-14     Completed Date:  2004-04-20     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  4719-27     Citation Subset:  IM    
Department of Biochemistry, Biophysics and Macromolecular Chemistry, University of Trieste, Via Giorgieri 1, I-34127 Trieste, Italy.
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MeSH Terms
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Candida albicans / enzymology*
Enzyme Inhibitors / chemistry,  pharmacology
Ethylenes / chemistry*,  pharmacology
HIV Protease Inhibitors / chemistry,  pharmacology
HIV-1 / enzymology*
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Peptides / chemistry*,  pharmacology*
Recombinant Proteins / antagonists & inhibitors
Structure-Activity Relationship
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Ethylenes; 0/HIV Protease Inhibitors; 0/Peptides; 0/Recombinant Proteins; 557-75-5/hydroxyethylene; EC 3.4.23.-/Aspartic Acid Endopeptidases

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