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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:
Danish National Research Foundation; Natural Science Foundation of China; Natural Science Foundation of the Fujian Province; Lundbeck Foundation; Carlsberg Foundation; Cancer Research Foundation of 1989
Grant/Contract Number:
26-331-6; 31161130356; 31170707; 31370737; 2012J05071; R83-A7826; 2012_01_0642; 2012T1G0023
OSTI ID:
1245843
Journal Information:
Journal of Medicinal Chemistry, Vol. 58, Issue 22; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 14 works
Citation information provided by
Web of Science

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Cited By (1)

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

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