Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming
| Autor: | Daniel J Ford, Henri M. H. Spronk, Wenyu Liu, Vishnu M. Sasi, Colin J. Jackson, Tilman M. Hackeng, Nisharnthi M Duggan, Pedro Pereira, Hiroaki Suga, Stijn M. Agten, Anneliese S. Ashhurst, Rene van Oerle, Jorge Ripoll-Rozada, Richard J. Payne, Joe A. Kaczmarski, Leo Corcilius, Toby Passioura, Sarah E. Fry |
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| Přispěvatelé: | Biochemie, RS: Carim - B01 Blood proteins & engineering, RS: Carim - B04 Clinical thrombosis and Haemostasis |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Factor XIIa
Peptide COAGULATION-FACTOR XII 01 natural sciences IN-VITRO SELECTION Serine Drug Discovery Messenger/chemistry Puromycin/chemistry chemistry.chemical_classification 0303 health sciences Chemistry Protein Stability Peptides Cyclic/chemistry Alanine scanning Cyclic peptide Biochemistry Genetic Code Molecular Medicine RNA Messenger/chemistry Kallikreins Puromycin Partial Thromboplastin Time Proteases Serine Proteinase Inhibitors Molecular Dynamics Simulation Peptides Cyclic VALIDATION 03 medical and health sciences Inhibitory Concentration 50 Structure-Activity Relationship MACROCYCLE INHIBITOR mRNA display Humans RNA Messenger Binding site 030304 developmental biology Gene Library Binding Sites Factor XIIa/antagonists & inhibitors Cyclic/chemistry 0104 chemical sciences Serine Proteinase Inhibitors/chemistry THROMBUS FORMATION 010404 medicinal & biomolecular chemistry Kallikreins/chemistry Prothrombin Time RNA Peptides GENERATION |
| Zdroj: | Journal of Medicinal Chemistry, 64(11), 7853-7876. American Chemical Society |
| ISSN: | 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00651 |
| Popis: | The contact system comprises a series of serine proteases that mediate procoagulant and proinflammatory activities via the intrinsic pathway of coagulation and the kallikrein-kinin system, respectively. Inhibition of Factor XIIa (FXIIa), an initiator of the contact system, has been demonstrated to lead to thrombo-protection and anti-inflammatory effects in animal models and serves as a potentially safer target for the development of antithrombotics. Herein, we describe the use of the Randomised Nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology to identify a series of potent and selective cyclic peptide inhibitors of FXIIa. Cyclic peptides were evaluated in vitro, and three lead compounds exhibited significant prolongation of aPTT, a reduction in thrombin generation, and an inhibition of bradykinin formation. We also describe our efforts to identify the critical residues for binding FXIIa through alanine scanning, analogue generation, and via in silico methods to predict the binding mode of our lead cyclic peptide inhibitors. |
| Databáze: | OpenAIRE |
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