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Publication Abstract from PubMed

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 muM) without measurable affinity to plasma kallikrein (Ki > 1000 muM). 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 muM). 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. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.

Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor.,Xu P, Xu M, Jiang L, Yang Q, Luo Z, Dauter Z, Huang M, Andreasen PA J Med Chem. 2015 Nov 25;58(22):8868-76. doi: 10.1021/acs.jmedchem.5b01128. Epub, 2015 Nov 12. PMID:26536069^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.