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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 <jats:italic>in vitro<\/jats:italic>, cellular based and <jats:italic>in vivo<\/jats:italic> mouse assays, several potent inhibitors of approximately one nanomolar inhibitory strength both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/srep16981","type":"journal-article","created":{"date-parts":[[2015,11,20]],"date-time":"2015-11-20T11:23:21Z","timestamp":1448018601000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Substrate-based inhibitors exhibiting excellent protective and therapeutic effects against Botulinum Neurotoxin A intoxication"],"prefix":"10.1038","volume":"5","author":[{"given":"Jiubiao","family":"Guo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinglin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Waichi Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,11,20]]},"reference":[{"key":"BFsrep16981_CR1","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/0968-0004(93)90065-U","volume":"18","author":"C Montecucco","year":"1993","unstructured":"Montecucco, C. & Schiavo, G. 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