Wei Yu, Fei Liu, Qianwen Guo, Bo Ouyang, Yanghong Zhuo, Yulan Liu, Songtao Liu, Chaoqi He, Xiyuan Zhu, Linwei Li, Shuai Yang, Shu Xu, Yuguang Mu, Muxing Liu, Yu Chen, Xu Feng, Jingjing Guo, Feng Zhang
Magnaporthe oryzae is a devastating fungal pathogen causing blast disease in rice and other crops, threatening global grain production and food security. Phenamacril (PHA) effectively inhibits Fusarium graminearum by targeting F. graminearum myosin I (FgMyoI). However, PHA shows limited activity against M. oryzae, despite the high sequence similarity between FgMyoI and M. oryzae myosin I (MoMyoI). Using our published PHA-FgMyoI complex structure as a template, we identified K378 in MoMyoI as a key determinant of insensitivity to PHA. Substitution of K378 with methionine, the corresponding residue in FgMyoI, markedly enhanced PHA-mediated inhibition of MoMyoI ATPase activity and improved PHA efficacy against M. oryzae. Guided by structure-based design, we synthesized PHA derivatives targeting MoMyoI. Among them, NJY-10 showed improved MoMyoI binding, ATPase inhibition, and protective efficacy against rice blast disease.