1. Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A
- Author
-
Jacobson, Alan R., Adler, Michael, Silvaggi, Nicholas R., Allen, Karen N., Smith, Genessa M., Fredenburg, Ross A., Stein, Ross L., Park, Jong-Beak, Mukherjee, Jean, Feng, Xiaochuan, Shoemaker, Charles B., Deshpande, Sharad S., Goodnough, Michael C., Malizio, Carl J., Johnson, Eric A., Pellett, Sabine, Tepp, William H., and Tzipori, Saul
- Subjects
Male ,0301 basic medicine ,Neurotoxins ,Biology ,Crystallography, X-Ray ,Toxicology ,Article ,Microbiology ,Rats, Sprague-Dawley ,Mice ,03 medical and health sciences ,In vivo ,Drug Discovery ,medicine ,Animals ,Protease Inhibitors ,Metalloprotease inhibitor ,Botulism ,Botulinum Toxins, Type A ,Cells, Cultured ,030102 biochemistry & molecular biology ,Muscles ,medicine.disease ,Botulinum toxin ,In vitro ,030104 developmental biology ,Toxicity ,Metalloproteases ,Antitoxin ,Ex vivo ,Muscle Contraction ,medicine.drug - Abstract
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.
- Published
- 2017
- Full Text
- View/download PDF