Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A. Toxicon 2017 Oct;137:36-47
Date
07/13/2017Pubmed ID
28698055Pubmed Central ID
PMC5694348DOI
10.1016/j.toxicon.2017.06.016Scopus ID
2-s2.0-85024473954 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.
Author List
Jacobson AR, Adler M, Silvaggi NR, Allen KN, Smith GM, Fredenburg RA, Stein RL, Park JB, Feng X, Shoemaker CB, Deshpande SS, Goodnough MC, Malizio CJ, Johnson EA, Pellett S, Tepp WH, Tzipori SAuthor
Nicholas R. Silvaggi PhD Assistant Professor in the Chemistry and Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AnimalsBotulinum Toxins, Type A
Cells, Cultured
Crystallography, X-Ray
Drug Discovery
Male
Metalloproteases
Mice
Muscle Contraction
Muscles
Neurotoxins
Protease Inhibitors
Rats, Sprague-Dawley
