Mechanism of Inhibition of Botulinum Neurotoxin Type a Light Chain by Two Quinolinol Compounds
Quinolinol-based compounds are a promising starting point for discovery of effective inhibitors of the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism of inhibition by quinolinol compounds facilitate interpretation of docking data and inhibitor optimization. In this study, a fluorogenic substrate of BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC50 values of 3.3 μM and 5.8 μM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors of BoNT/A LC with inhibition constants (KI) 3.2 μM and 6.2 μM for MSU58 and MSU84, respectively. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding of 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.
MSU Digital Commons Citation
Minnow, Yacoba V.T.; Goldberg, Ronald; Tummalapalli, Sreedhar R.; Rotella, David; and Goodey, Nina, "Mechanism of Inhibition of Botulinum Neurotoxin Type a Light Chain by Two Quinolinol Compounds" (2017). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 243.