Date Approved
2019
Degree Type
Open Access Senior Honors Thesis
Department or School
Chemistry
First Advisor
Cory Emal
Second Advisor
Hedeel Evans
Third Advisor
Deborah Heyl-Clegg
Abstract
Plasminogen activator inhibitor type-I (PAI-I ) is a serpin superfamily member protein that acts as the major inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). At physiological levels, PAI-I plays an active role in regulating fibrinolysis, the process of normal blood clot degradation. Pathological levels of PAI-I have been linked to multiple health ailments: fibrosis, heart disease, cancer, and obesity. In recent years, PAI-1 has been the subject of targeted drug design. In this study, we identified a class of polyphenol compounds as the most capable of maintaining its inhibitory efficiency against vitronectin bound PAI-I in buffer and plasma. Additionally, a previously reported class of biphenyl amide PAI-I inhibitors was structurally probed to determine the pharmacophore. We provide evidence supporting the anti-PAI-I pharmacophore as the carboxylic acid moiety, observing modifications to this group significantly reduces potency. Furthermore, to assess if the in vivo metabolites of the biphenyl amides were active against PAl-1, structurally inspired metabolites were tested and found to yield no activity.
Recommended Citation
Powers, Justin A., "An investigation of the nature of plasminogen activator inhibitor type-I (PAI-I) to improve upon known small molecule inhibitors" (2019). Senior Honors Theses and Projects. 634.
https://commons.emich.edu/honors/634
