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Design, synthesis and antithrombin activity for conformationally restricted analogs of peptide anticoagulants based on the C-terminal region of the leech peptide, hirudin.

Authors
  • Krstenansky, J L
  • Owen, T J
  • Yates, M T
  • Mao, S J
Type
Published Article
Journal
Biochimica et Biophysica Acta
Publisher
Elsevier
Publication Date
Nov 02, 1988
Volume
957
Issue
1
Pages
53–59
Identifiers
PMID: 3179320
Source
Medline
License
Unknown

Abstract

Synthetic peptides cyclized via disulfide linkages have been synthesized as conformationally restricted analogs of a novel class of antithrombotic peptides that inhibit fibrinogen cleavage by binding to a non-enzymatic site on thrombin. Several conformational models for these inhibitors have been considered and cyclic analogs were synthesized to test their validity. Compounds designed on an alpha-helical model yielded several cyclic analogs that retained antithrombin activity. [D-Cys58, Cys61]-hirudin54-65, 5, and [D-Cys60, Cys63]-hirudin54-65, 6, had IC50 values of 26 and 30 microM, respectively, in an in vitro clot assay compared with a value of 3.7 microM for the linear hirudin54-65.

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