Premium
Design and synthesis of acidic dipeptide hydroxamate inhibitors of procollagen C ‐proteinase
Author(s) -
Ovens Annabel,
Joule John A.,
Kadler Karl E.
Publication year - 2000
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/1099-1387(200009)6:9<489::aid-psc282>3.0.co;2-k
Subject(s) - procollagen peptidase , dipeptide , chemistry , cleavage (geology) , biochemistry , matrix metalloproteinase , aspartic acid , extracellular matrix , peptide , stereochemistry , enzyme , ic50 , in vitro , amino acid , microbiology and biotechnology , biology , paleontology , fracture (geology)
Procollagen C ‐proteinase (PCP) is essential for the cleavage of procollagen to collagen in the extracellular matrix of animals and is, therefore, of major relevance to studies of ectopic deposition of collagen during fibrosis. In this study, we describe the design and synthesis of acidic side chain hydroxamate dipeptide inhibitors of PCP having IC 50 values in the range 0.1–10 μ m that mimic the location of aspartic acid residues in the P1′ and P2′ positions (i.e. immediately C ‐terminal) of the PCP cleavage site in procollagen. Assays of PCP using purified human type I procollagen (a natural substrate of PCP) showed that the structure activity relationship of the inhibitors was improved with a glutamic acid mimic at the P1′ position. The results also showed that the presence of an acidic side chain at the P2′ position was not necessary for PCP inhibition. Marimastat and BB3103, which are highly effective inhibitors of matrix metalloproteinases and ADAMS proteinases, respectively, did not inhibit PCP. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.