抗药性
化学
效力
乙酰胆碱酯酶
埃及伊蚊
登革热病毒
合理设计
体内
酶
登革热
计算生物学
生物化学
药理学
毒理
生物
病毒学
生物技术
体外
遗传学
生态学
幼虫
作者
Sofie Knutsson,Cecilia Engdahl,Rashmi Kumari,Nina Forsgren,Cecilia M. Lindgren,Tomas Kindahl,Stanley Kitur,Lucy Wachira,Luna Kamau,Fredrik Ekström,Anna Linusson
标识
DOI:10.1021/acs.jmedchem.8b01060
摘要
Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure-activity relationship analyses and molecular dynamics simulations of inhibitor-protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.
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