Pioneering protein degradation for agricultural applications.

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作者:Morgan Gina L, Dickson Hamilton, Ford Breanna, Noras Aleksandra, Bremmer Steven C, Watts Brian E, Pilotte Joseph, Anderson Ed, Sullivan Eric D, Stoner Mikayla, Ouedraogo Daniel, Saltzberg Daniel J, Pothula Karunakar R, Ingram Paul, Catalano John, Lillich Melina, Kolbe Carl-Christian, Pfeiffer Anne, Ladner Christopher C, Gattis Sam, Speake Jason, Voss Stephanie, Broccio Kelly, Fourches Denis
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.

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