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Bicyclic Peptide Inhibitor Reveals Large Contact Interface with a Protease Target

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Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
Department of Biological Chemistry, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy
Venetian Institute of Molecular Medicine (VIMM), Via Giuseppe Orus 2, 35129 Padua, Italy
§ Laboratory of Molecular Biology, Medical Research Council, Hills Road, Cambridge CB2 0QH, U.K.
Cite this: ACS Chem. Biol. 2012, 7, 5, 817–821
Publication Date (Web):February 3, 2012
https://doi.org/10.1021/cb200478t
Copyright © 2012 American Chemical Society

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    Abstract

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    From a large combinatorial library of chemically constrained bicyclic peptides we isolated a selective and potent (Ki = 53 nM) inhibitor of human urokinase-type plasminogen activator (uPA) and crystallized the complex. This revealed an extended structure of the peptide with both peptide loops engaging the target to form a large interaction surface of 701 Å2 with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics.

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    Additional results on the affinity maturation of UK18, X-ray data collection and refinement statistics, additional views of the structure as well as a detailed discussion of the structure and the molecular interactions between the bicyclic peptide and the protease; complete experimental details as well as a characterization and validation of linear and cyclic peptides. This material is available free of charge via the Internet at http://pubs.acs.org.

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