Date of Award
Master of Science (MS)
College of Science and Mathematics
Chemistry and Biochemistry
Thesis Sponsor/Dissertation Chair/Project Chair
Quinolinol-based compounds are a promising starting point for discovery o f effective inhibitors o f the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism o f inhibition by quinolinol compounds facilitate interpretation o f docking data and inhibitor optimization. In this study, a fluorogenic substrate o f BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC50 values of 3.3 uM and 5.8 uM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors o f BoNT/A LC with inhibition constants (KI) 3.2 uM and 6.2 uM for MSU58 and MSU84, respectively. The kinetic rate constant for substrate and inhibitor binding and release were also determined. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding o f the substrate. This is the first study to report the competitive inhibition of BoNT/A LC by quinolinol compounds. These data help define the inhibitor binding pocket and, along with structure activity relationship studies, provide immediate direction for further compound synthesis.
Minnow, Yacoba Vroom Teschemaker, "The Mechanism of Inhibition of Botulinum Neurotoxin Type A by Two Quinolinol Compounds" (2017). Theses, Dissertations and Culminating Projects. 548.