Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.
School of Bioengineering, Dalian University of Technology, Dalian, Liaoning 116024, People's Republic of China.
J Agric Food Chem. 2021 Jul 14;69(27):7534-7544. doi: 10.1021/acs.jafc.0c08119. Epub 2021 Jun 29.
The insect chitinase ChtI from the agricultural pest (Asian corn borer) is a promising target for green insecticide design. ChtI is a critical chitinolytic enzyme for the cuticular chitin degradation at the stage of molting. In this study, piperine, a natural amide compound isolated from black pepper, L., was discovered for the first time to have inhibitory activity toward ChtI. The compound-enzyme interaction was presumed to take place between the piperine benzo[][1,3] dioxole skeleton and subsite -1 of the substrate-binding pocket of ChtI. Hence, on the basis of the deduced inhibitory mechanism and crystal structure of the substrate-binding cavity of ChtI, compounds - were designed and synthesized by introducing a butenolide scaffold into the lead compound piperine. The enzymatic activity assay indicated that compounds - ( = 1.03-2.04 μM) exhibited approximately 40-80-fold higher inhibitory activity than the lead compound piperine () ( = 81.45 μM) toward ChtI. The inhibitory mechanism of the piperonyl butenolide compounds was elucidated by molecular dynamics, which demonstrated that the introduced butenolide skeleton improved the binding affinity to ChtI. Moreover, the activity assay indicated that these compounds also displayed moderate insecticidal activity toward . This work introduces the natural product piperine as a starting point for the development of novel insecticides targeting ChtI.
来自农业害虫（亚洲玉米螟）的昆虫几丁质酶 ChtI 是绿色杀虫剂设计的有前途的靶标。ChtI 是蜕皮阶段几丁质降解过程中关键的几丁质水解酶。在这项研究中，首次发现从黑胡椒中分离出的天然酰胺化合物胡椒碱对 ChtI 具有抑制活性。该化合物与酶的相互作用被认为发生在胡椒碱的苯并[][1,3]二恶烷骨架和 ChtI 的底物结合口袋的亚位点-1 之间。因此，基于推断的抑制机制和 ChtI 底物结合腔的晶体结构，通过将丁烯内酯支架引入先导化合物胡椒碱，设计并合成了化合物 - 。酶活性测定表明，化合物 - （= 1.03-2.04 μM）对 ChtI 的抑制活性比先导化合物胡椒碱（= 81.45 μM）高约 40-80 倍。通过分子动力学阐明了胡椒基丁烯内酯化合物的抑制机制，表明引入的丁烯内酯骨架提高了与 ChtI 的结合亲和力。此外，[对 的]活性测定表明，这些化合物对 也表现出中等的杀虫活性。这项工作将天然产物胡椒碱作为开发针对 ChtI 的新型杀虫剂的起点。
