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Title: Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor

Journal Article · · Journal of Medicinal Chemistry
 [1];  [2];  [2];  [1];  [3];  [3];  [2];  [1]
  1. Aarhus Univ. (Denmark)
  2. Chinese Academy of Sciences, Fuzhou (China)
  3. Argonne National Lab. (ANL), Argonne, IL (United States)
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All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 μM) without measurable affinity to plasma kallikrein (Ki > 1000 μM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 μM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Furthermore, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Cancer Research Foundation of 1989; Carlsberg Foundation; Danish National Research Foundation; Lundbeck Foundation; Natural Science Foundation of China; Natural Science Foundation of the Fujian Province
OSTI ID:
1245843
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 22 Vol. 58; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Structural Principles in the Development of Cyclic Peptidic Enzyme Inhibitors journal January 2017

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
chemical specificity
inhibition
inhibitors
monomers
peptides and proteins