As the world of agrochemicals is entering a race for efficient and safe modalities, there is an urgent and specific need for entirely new modes of action. Proteolysis-targeting chimeras (PROTACs) recruit naturally occurring E3 ubiquitin ligases to induce potent and selective degradation of protein targets via the ubiquitin-proteasome system (UPS). Herein, we demonstrate the degradative abilities of the insect VHL (von Hippel-Lindau) E3 ligase, making it the first PROTAC-ready ligase for agriculture applications. In doing so, we developed VHL-recruiting PROTACs capable of degrading fall armyworm (Spodoptera frugiperda) sfBRD3 protein with potencies as high as >80% in Sf9 cells and >60% in larvae. We also successfully designed, optimized, and tested PROTACs that significantly degraded sfWDS protein in both cells and whole organisms. This proof-of-concept study pioneers the use of PROTACs for agricultural applications and establishes this modality as a promising, disruptive alternative to traditional small molecule inhibitors.

© 2025. The Author(s).

随着农业化学品领域正在进入高效和安全模式的竞争，迫切需要全新的作用方式。蛋白酶靶向嵌合体（PROTAC）通过招募自然存在的E3泛素连接酶，利用泛素-蛋白酶体系统（UPS），诱导蛋白质目标的强烈且特异性的降解。在此，我们展示了昆虫VHL（冯·希佩尔-林道）E3连接酶的降解能力，使其成为首个适用于农业应用的PROTAC就绪连接酶。为此，我们开发了能够招募VHL的PROTAC，在Sf9细胞中可使秋粘虫（Spodoptera frugiperda）的sfBRD3蛋白降解率高达超过80%，在幼虫中的降解率也超过了60%。此外，我们还成功设计、优化并测试了能够在细胞和整个生物体中显著降低sfWDS蛋白水平的PROTACs。这项概念验证研究表明了将PROTAC应用于农业领域的开创性，并确立了这一模式作为传统小分子抑制剂的一种有前景且具有颠覆性的替代方案。

© 2025. The Author(s).