Synthesis and activity evaluation of selenazole-coupled CPI-1 irreversible bifunctional inhibitors for botulinum toxin A light chain

Abstract

A series of novel conjugates of benzoselenazole or selenazole and CPI-1 were designed, synthesized, and evaluated for inhibitory activities against the botulinum neurotoxin A (BoNT/A) light chain (LC) and BoNT/A in vivo. The results show that these compounds exhibit potent inhibitory activities to the LC with IC50 of 0.5–4.1 µM. The reaction kinetics and the mass spectra of the reaction products of LC with benzoselenazole- or selenazole- coupled CPI-1 demonstrate that the benzoselenazole group of most inhibitors is coupled to the LC of BoNT/A. These data indicate that the CPI-1 conjugates can inhibit both the active center of BoNT/A LC as well as Cys165, therefore functioning as irreversible bifunctional inhibitors. The detoxification activities in vivo show that one of the benzoselenazole-CPI-1 compounds prolongs the survival time of mice challenged by 2 × LD50 of BoNT/A. This work provides a new strategy to design potent antidotes of BoNT/A.