title: Substrate-based inhibitors exhibiting excellent protective and therapeutic effects against Botulinum Neurotoxin A intoxication.
abstract: Potent inhibitors to reverse Botulinum neurotoxins (BoNTs) activity in neuronal cells are currently not available. A better understanding of the substrate recognition mechanism of BoNTs enabled us to design a novel class of peptide inhibitors which were derivatives of the BoNT/A substrate, SNAP25. Through a combination of in vitro, cellular based, and in vivo mouse assays, several potent inhibitors of approximately one nanomolar inhibitory strength both in vitro and in vivo have been identified. These compounds represent the first set of inhibitors that exhibited full protection against BoNT/A intoxication in mice model with undetectable toxicity. Our findings validated the hypothesis that a peptide inhibitor targeting the two BoNT structural regions which were responsible for substrate recognition and cleavage respectively could exhibit excellent inhibitory effect, thereby providing insight on future development of more potent inhibitors against BoNTs.
authors.affiliation: Shenzhen Key lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, P. R. China.|State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
authors.forename: Jiubiao
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People's Republic of China.
authors.forename: Jinglin
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Ji
authors.affiliation: Shenzhen Key lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, P. R. China.|State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
authors.forename: Edward
authors.initials: E
authors.lastname: Waichi Chan
authors.affiliation: Shenzhen Key lab for Food Biological Safety Control, Food Safety and Technology Research Center, Hong Kong PolyU Shen Zhen Research Institute, Shenzhen, P. R. China.|State Key Lab of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D001904:Botulinum Antitoxin / Q000737:chemistry / Q000494:pharmacology*; D019274:Botulinum Toxins, Type A / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001906:Botulism / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D045744:Cell Line, Tumor; D051379:Mice; D008958:Models, Molecular; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D050825:Synaptosomal-Associated Protein 25 / Q000737:chemistry / Q000378:metabolism
chemical_list: D001904:Botulinum Antitoxin; D009498:Neurotoxins; D010455:Peptides; D050825:Synaptosomal-Associated Protein 25; D019274:Botulinum Toxins, Type A