Design and synthesis of acidic dipeptide hydroxamate inhibitors of procollagen C‐proteinase

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 IC50 values in the range 0.1–10 μm 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.

[1]  S. Friedman.  Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury* , 2000, The Journal of Biological Chemistry.

[2]  W. Bode,et al.  1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase-8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with a distinct selectivity profile. , 1997, European journal of biochemistry.

[3]  P. McCann,et al.  Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat. , 1997, Pharmacology & therapeutics.

[4]  J. A. Chapman,et al.  Enzymic control of collagen fibril shape. , 1996, Journal of molecular biology.

[5]  T L Blundell,et al.  X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily. , 1996, Structure.

[6]  D. Greenspan,et al.  Bone Morphogenetic Protein-1: The Type I Procollagen C-Proteinase , 1996, Science.

[7]  R. Bast,et al.  Regulation of tumour necrosis factor-α processing by a metalloproteinase inhibitor , 1994, Nature.

[8]  R. Wolz.  A kinetic comparison of the homologous proteases astacin and meprin A. , 1994, Archives of biochemistry and biophysics.

[9]  W. Bode,et al.  Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc‐binding environments (HEXXHXXGXXH and Met‐turn) and topologies and should be grouped into a common family, the ‘metzincins’ , 1993, FEBS letters.

[10]  W. Bode,et al.  Implications of the three-dimensional structure of astacin for the structure and function of the astacin family of zinc-endopeptidases. , 1993, European journal of biochemistry.

[11]  R. Beynon,et al.  The astacin family of metalloendopeptidases , 1991, The Journal of biological chemistry.

[12]  A. Berger,et al.  On the size of the active site in proteases. I. Papain. , 1967, Biochemical and biophysical research communications.

[13]  R. Wolz,et al.  Meprins A and B. , 1995, Methods in enzymology.