Discovery and characterization of small molecule inhibitors of cystathionine gamma‐synthase with <i>in planta</i> activity

Bloch, Itai; Haviv, Hadar; Rapoport, Irena; Cohén, Esther; Shushan, Rotem Shelly Ben; Dotan, Nesly; Sher, Inbal; Hacham, Yael; Amir, Rachel; Gal, Maayan

doi:10.1111/pbi.13591

Cited by 2 publications

(2 citation statements)

References 81 publications

(94 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The third motivation is that within the realm of PPI, those involved in the synthesis of amino acids, and in particular the essential ones for mammals, are an attractive target for the development of biosafe herbicides. Indeed, we previously showed that molecules inhibiting the methionine biosynthesis pathway are inhibitory in-planta 11 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pesticide chemical leads inhibiting protein-protein interactions

Ben Shushan,

Cohen,

Ben Naim

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Pesticides, especially herbicides, have revolutionized agriculture by providing energy-efficient solutions for pest control that replaces labor-intensive cultivation methods. However, the widespread evolution of pesticide resistance poses a significant challenge to current agriculture. Most pesticides function by binding to specific pockets on target enzymes, enabling a single mutation to confer resistance. An alternative approach is the disruption of protein-protein interactions (PPI), thus for resistance to occur, it requires complementary mutations on both interacting partners. Despite extensive efforts, no herbicides with new modes of action have been commercialized for decades. Thus, we focused on 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 plant enzymes involved in the biosynthesis of the essential amino acid cysteine. Using 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. Subsequently, we conducted chemical optimizations to evaluate biophysical enzyme disruption, followed by cellular and in-planta activity in plants. These new compounds described herein can serve as promising starting points for further optimization as herbicides acting on a new mode of action.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Interfering with the PPIs involved in the biosynthesis of essential amino acids is an attractive approach for the design of new herbicides 11 . Cysteine has a significant role in plant growth and development as it is the primary source of the sulfur moiety in sulfur-containing compounds.…”

Section: Inhibiting Protein-protein Interactions: Bringing Vast New T...mentioning

confidence: 99%

Pesticide chemical leads inhibiting protein-protein interactions

Ben Shushan,

Cohen,

Ben Naim

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

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

Ben‐Shushan,

Cohen,

Ben‐Naim

et al. 2024

Pest Management Science

View full text Add to dashboard Cite

BACKGROUNDThe 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.RESULTSBy 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.CONCLUSIONThese 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. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

show abstract

Discovery and characterization of small molecule inhibitors of cystathionine gamma‐synthase with in planta activity

Cited by 2 publications

References 81 publications

Pesticide chemical leads inhibiting protein-protein interactions

Pesticide chemical leads inhibiting protein-protein interactions

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

Contact Info

Product

Resources

About