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Synthesis of cysteine proteinase inhibitors structurally based on the proteinase interacting N-terminal region of human cystatin C.

Authors
  • Grubb, A
  • Abrahamson, M
  • Olafsson, I
  • Trojnar, J
  • Kasprzykowska, R
  • Kasprzykowski, F
  • Grzonka, Z
Type
Published Article
Journal
Biological chemistry Hoppe-Seyler
Publication Date
May 01, 1990
Volume
371 Suppl
Pages
137–144
Identifiers
PMID: 2400574
Source
Medline
License
Unknown

Abstract

Peptides spanning the entire, or part of, the Gly4-Glu21 segment of the human cysteine proteinase inhibitor cystatin C have been synthesized. Peptides containing residues on the N-terminal side of Gly11 were rapidly cleaved by papain at the bond Gly11-Gly12 whereas a peptide starting at residue Gly11 was not, thus demonstrating 1. that the N-terminal segment of cystatin C has an amino acid sequence that would allow rapid interaction between this segment and the substrate pocket of papain and, if this interaction takes place, that 2. the cystatin C residue Gly11 would be in the P1 position, and 3. the major interaction would be between residues Arg8-Val10 and the papain substrate pocket subsites S4, S3 and S2, respectively. Several modified peptide derivatives containing either diazomethane groups or peptide bond isosters were synthesized based on the structure of the Leu9-Gly11 segment of cystatin C and tested for their cysteine proteinase inhibiting capacity. The peptidyl derivatives, t-butyloxycarbonyl-valyl-glycyl-diazomethane and benzyloxycarbonyl-leucyl-valyl-glycyl-diazomethane irreversible inhibited the cysteine proteinases papain, bovine cathepsin B and streptococcal proteinase, but did not influence the activity of serine, aspartic or metallo-proteinases.

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