Substrate-Guided Design of Selective FXIIa Inhibitors Based on the Plant-Derived Momordica cochinchinensis Trypsin Inhibitor-II (MCoTI-II) Scaffold

Joakim E Swedberg; Tunjung Mahatmanto; Hafiza Abdul Ghani; Simon J de Veer; Christina I Schroeder; Jonathan M Harris; David J Craik

doi:10.1021/acs.jmedchem.6b00557

Substrate-Guided Design of Selective FXIIa Inhibitors Based on the Plant-Derived Momordica cochinchinensis Trypsin Inhibitor-II (MCoTI-II) Scaffold

J Med Chem. 2016 Aug 11;59(15):7287-92. doi: 10.1021/acs.jmedchem.6b00557. Epub 2016 Aug 1.

Authors

Joakim E Swedberg¹, Tunjung Mahatmanto¹, Hafiza Abdul Ghani¹, Simon J de Veer², Christina I Schroeder¹, Jonathan M Harris², David J Craik¹

Affiliations

¹ Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
² Institute of Health and Biomedical Innovation, Queensland University of Technology , Brisbane Queensland 4059, Australia.

PMID: 27434175
DOI: 10.1021/acs.jmedchem.6b00557

Abstract

Thrombosis is a leading cause of morbidity and mortality associated with cardiovascular diseases. Inhibition of factor XIIa (FXIIa) provides thrombus protection without bleeding complications. Here, we defined the extended substrate specificity of FXIIa and its close homologue factor Xa and used these data, together with inhibitor-based and structure-guided methods, to engineer selective FXIIa inhibitors based on Momordica cochinchinensis trypsin inhibitor-II.

MeSH terms

Blood Proteins / chemical synthesis
Blood Proteins / chemistry
Blood Proteins / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Factor XIIa / antagonists & inhibitors*
Factor XIIa / metabolism
Humans
Molecular Dynamics Simulation
Momordica / chemistry*
Oligopeptides / chemical synthesis
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Structure-Activity Relationship

Substances

Blood Proteins
Oligopeptides
factor XIIa inhibitor
Factor XIIa