Discovering new mode-of-action pesticide leads inhibiting protein–protein interactions: example targeting plant O-acetylserine sulfhydrylase

Rotem Shelly Ben-Shushan, Elad Cohen, Noam Ben-Naim, Eytan Amram, Jonathan Gressel, Dotan Peleg, Nesly Dotan, Itai Bloch, Maayan Gal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: The widespread evolution of pesticide resistance poses a significant challenge to current agriculture, necessitating the discovery of molecules with new modes of action. Despite extensive efforts, no major molecules with new modes of action have been commercialized for decades. Most pesticides function by binding to specific pockets on target enzymes, enabling a single target site mutation to confer resistance. An alternative approach is the disruption of protein–protein interactions (PPI), which require complementary mutations on both interacting partners for resistance to occur. Thus, our aim is the discovery and design of small-molecule inhibitors that target the interface of the PPI complex of O-acetylserine sulfhydrylase (OASS) and serine acetyltransferase (SAT), key obligatory interacting plant enzymes involved in the biosynthesis of the amino acid cysteine. RESULTS: By employing in silico filtering techniques on a virtual library of 30 million small molecules, we identified initial hits capable of binding OASS and interfering with its interaction with a peptide derived from SAT with a half-maximal inhibitory concentration (IC50) of 34 μm. Subsequently, we conducted molecular chemical optimizations, generating an early lead molecule (PJ4) with an IC50 value of 4 μm. PJ4 successfully inhibited the germination of Arabidopsis thaliana seedlings and inhibited clover growth in a pre-emergence application at an effective concentration of 4.6 kg ha−1. CONCLUSION: These new compounds described herein can serve as promising leads for further optimization as herbicides with a new mode-of-action. This technology can be used for discovering new modes of action chemicals inhibiting all pest groups.

Original languageEnglish
Pages (from-to)6424-6436
Number of pages13
JournalPest Management Science
Volume80
Issue number12
DOIs
StatePublished - Dec 2024

Funding

FundersFunder number
Migal–Galilee Research Institute
Israel Innovation Authority
Bayer-Trendlines Ag Innovation Fund
Bayer‐Trendlines Ag Innovation Fund

    Keywords

    • O-acetylserine sulfhydrylase (OASS)
    • cysteine biosynthesis inhibition
    • herbicide discovery
    • protein–protein interactions
    • serine acetyltransferase (SAT)

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