Open AccessDesign of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor
Author(s) -
Peng Xu,
Mingming Xu,
Longguang Jiang,
Qinglan Yang,
Zhipu Luo,
Zbigniew Dauter,
Mingdong Huang,
Peter A. Andreasen
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b01128
Subject(s) - proteases , chemistry , kallikrein , serine protease , serine , peptide , urokinase , plasminogen activator , biochemistry , enzyme inhibitor , protease inhibitor (pharmacology) , serine proteinase inhibitors , enzyme , protease , stereochemistry , biology , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load , genetics , immunology , endocrinology
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. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.