典型文献
Discovery of a Potent Botulinum Neurotoxin A Inhibitor ZM299 with Effective Protections in Botulism Mice
文献摘要：
Botulinum neurotoxins serotype A(BoNT/A)is the deadliest toxins known to humans and the"Category A"agent for bioterrorism.Over the past 20 years,significant efforts have been put forth to develop effective inhibitors of BoNT/A.Unfortunately,few identified inhibitors possess noteworthy efficacy against BoNT/A in vivo.Here,we performed a high-throughput virtual screening based on the structure-based docking simulations and found a novel potent scaffold 2-thionicotinate that inhibits the BoNT/A light chain(LC).We then synthesized and optimized a novel series of 2-thionicotinate derivatives and comprehensively evaluated their activity against BoNT/A in vitro and in vivo.An optimized compound ZM299 effectively exhibits anti-BoNT/A activity in primary neurons and displayed remarkably therapeutic efficacy against BoNT/A in vivo,which could raise the survival rate of intoxicated mice to 100％(12/12)after lethal doses of BoNT/A exposures.These findings demonstrate that 2-thionicotinates is a promising scaffold for producing more effec-tive anti-BoNT/A analogs,and compound ZM299 is worthy of further preclinical evaluation as a drug candidate for the treatment of botulism.
文献关键词：
中图分类号：
作者姓名：
Jianxin Wang;Yuelin Wu;Deyan Luo;Chunlin Zhuang;Nianzhi Ning;Yanming Zhang;Zhili He;Jie Gao;Zhanying Hong;Xiguo Xv;Wannian Zhang;Tao Li;Zhenyuan Miao;Hui Wang
作者机构：
State Key Laboratory of Pathogens and Biosecurity,Beijing Institute of Microbiology and Epidemiology,Beijing 100071,China;School of Pharmacy,Second Military Medical University,325 Guohe Road,Shanghai 200433,China
文献出处：
引用格式：
[1]Jianxin Wang;Yuelin Wu;Deyan Luo;Chunlin Zhuang;Nianzhi Ning;Yanming Zhang;Zhili He;Jie Gao;Zhanying Hong;Xiguo Xv;Wannian Zhang;Tao Li;Zhenyuan Miao;Hui Wang-.Discovery of a Potent Botulinum Neurotoxin A Inhibitor ZM299 with Effective Protections in Botulism Mice)[J].中国化学（英文版）,2022(03):357-364
A类：
Neurotoxin,ZM299,Protections,Botulism,bioterrorism,thionicotinate,thionicotinates,botulism
B类：
Discovery,Potent,Botulinum,Inhibitor,Effective,Mice,neurotoxins,serotype,BoNT,deadliest,known,humans,Category,agent,Over,past,years,significant,efforts,have,been,forth,develop,inhibitors,Unfortunately,few,identified,possess,noteworthy,efficacy,against,vivo,Here,we,performed,high,throughput,virtual,screening,structure,docking,simulations,found,novel,potent,scaffold,that,inhibits,light,chain,LC,We,then,synthesized,optimized,series,derivatives,comprehensively,evaluated,their,activity,vitro,An,compound,effectively,exhibits,anti,primary,neurons,displayed,remarkably,therapeutic,which,could,raise,survival,intoxicated,mice,after,lethal,doses,exposures,These,findings,demonstrate,promising,producing,more,analogs,further,preclinical,evaluation,drug,candidate,treatment
AB值：
0.562207
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