Targeted Protein Degradation for Agricultural Applications: Rationale, Challenges, and Outlook.

Abstract

Farmers urgently need novel technologies to ensure global food security for the rapidly expanding population, yet crop protection has seen little innovation in decades. Mounting regulatory pressures, pest resistance, and environmental concerns are driving demand for novel sustainable solutions. Beyond traditional small molecule active ingredients, very few alternative modalities (e.g., peptides, RNAi, biopesticides) have reached the market. Meanwhile, targeted protein degradation (TPD) has emerged as a breakthrough modality for human therapeutics, with numerous proteolysis-targeting chimeras (PROTACs) and molecular glues (MGs) advancing through clinical trials. Those compounds induce potent and selective degradation of protein targets via the ubiquitin-proteasome system (UPS). Recently, PROTACs have been shown to function in both insect cells and in whole insect organisms, marking a pivotal step toward their use as next-generation crop protection solutions. In this perspective, we showcase the rationale, key challenges, and potential breadth of applications of targeted protein degraders for agricultural purposes. The TPD technology is a promising and potentially disruptive alternative to traditional small molecule inhibitors in agriculture.