基于氧化固醇结合蛋白结构的高活性及反抗性杀菌剂的合理设计

卵菌可对农作物造成毁灭性危害，并引起世界范围内高达百亿美元的经济损失。氟噻唑吡乙酮是一种对卵菌有着显著抑制效果的全新农用杀菌剂，该分子通过抑制氧化固醇结合蛋白(OSBP)达到杀菌效果，这也是唯一商品化的OSBP抑制剂。但是，该化合物作用靶点单一，存在着较高的抗性风险。因此，如何开发骨架和作用方式新颖的OSBP抑制剂是该领域中的重大课题。为此，本项目拟综合运用分子模拟、有机合成、化学生物学等多学科前沿技术，建立OSBP计算模型，深入研究氟噻唑吡乙酮及其类似物与敏感型OSBP及G769W突变体的相互作用方式，开展基于结构的新型OSBP抑制剂的分子设计，通过“分子设计－抗性预测－有机合成－活性测试－模型优化”的研究循环，最终获得1~2个活性更高、抗性风险更低、结构更为新颖的OSBP杀菌剂。这也是迄今为止，首次针对卵菌开展的基于OSBP结构的抑制剂合理设计研究。

Plant-pathogenic oomycetes cause devastating diseases affecting crops and losses as high as $10 billion worldwide each year. In recent years, it is urgent to develop a super-efficient ligand to overcome the fungicide resistance in oomycetes. Oxathiapiprolin is a new agricultural product showing extremely high activity against a range of plant pathogenic oomycetes. It takes the effect by inhibiting the oxidizing sterol-binding protein (OSBP). However, the single target of this compound increases the risk of resistance. Therefore, the development of OSBP inhibitors with novel backbones and mechanisms of action has been a long-time project in this field. Hence, the molecular simulation, organic synthesis, and chemical biology will be integrated to carry out this project: establish the OSBP model, study the interaction mechanism of Oxathiapiprolin and its analogs with OSBP and G769W mutant, and perform structure-based drug design. Through the "Rational Design-Resistance Prediction-Organic Synthesis-Activity Assay-Model Optimization " multi-round research cycle, we strive to obtain 1~2 novel fungicide leads targeted to OSBP with excellent activity and low resistance risk. This is the first time to propose the rational design of fungicides based on OSBP structure to oomycetes until now.