Drug Discovery for Thirsty Crops

Lozano‐Juste, Jorge; García-Maquilón, Irene; Ruiz-Partida, Rafael; Rodriguez, Pedro L.

doi:10.1016/j.tplants.2020.07.001

Cited by 12 publications

(11 citation statements)

References 11 publications

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“…Whilst modifying the cyclohexenone moiety of ABA via stabilization or further substitution has attracted considerable synthetic interest due its potential to prevent formation of the catabolite phaseic acid, [13][14][15][16][17][18][19][20][21] a surprisingly limited number of studies has been made so far to investigate open-chain analogues of ABA or synthetic agonists. Recently, we have shown that cyano-cyclopropyl groups in ABA analogues 2 a-c served as isosteres of the cyclohexanone moiety giving rise to compounds with strong activity in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Exploration of Abscisic Acid Receptor Agonists Against Dought Stress by Adding Constraint to a Tetrahydroquinoline‐Based Lead Structure

et al. 2021

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New oxotetrahydroquinolinyl-and oxindolinyl sulfonamides interacting with RCAR/(PYR/PYL) receptor proteins were identified as lead structures against drought stress in crops starting from protein docking studies of a sulfonamide lead structure, followed by in-depth SAR studies. Optimized five to six step synthetic approaches via substituted amino oxo-tetrahydroquinolines and amino oxo-indolines as essential intermediates gave access to the envisaged oxo-tetrahydroquinolinyl and oxindolinyl sulfonamides. Whilst oxo-tetrahydroquinolinyl sulfonamides with additional carbon substituents or spiro-cycloalkyl groups exhibited only low to moderate target affinities, the corresponding spiro-oxindolinyl and oxo-tetrahydroquinolinyl sulfonamides carrying optimized N-substituents revealed strong interactions with RCAR/(PYR/PYL) receptor proteins in Arabidopsis thaliana. Remarkably, the in vitro activity observed for these new compounds was on the same level as observed for the naturally occurring plant hormone in line with strong efficacy against drought stress in-vivo (canola and wheat as broad-acre crops).

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Section: Introductionmentioning

confidence: 99%

Synthesis and Exploration of Abscisic Acid Receptor Agonists Against Dought Stress by Adding Constraint to a Tetrahydroquinoline‐Based Lead Structure

et al. 2021

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“…Quinabactin is more efficient than pyrabactin in regulating the ABA response and is known to affect plant vegetative responses, especially adaptive responses that are essential for crop quality and quantity. Cyanabactin treatment significantly affects stomatal conductance and regulates ABA gene expression (Vaidya et al, 2017), while opabactin is currently the most effective tool for manipulating efficiency of water use (Vaidya et al, 2019;Lozano-Juste et al, 2020). Mandipropamid is another example of a compound that has the ability to activate an engineered PYR1 receptor and has significant potential for the modulation of ABA signaling in crops (Park et al, 2015;Rodriguez and Lozano-Juste, 2015).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Inhibitors of a Plant Group A Protein Phosphatase Type 2C Using a Combined In Silico and Biochemical Approach

et al. 2020

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Type 2C protein phosphatases (PP2Cs) of group A play a significant role in the regulation of various processes in plants including growth, development, ion transport, and stress acclimation. In this study, we selected potential PP2C group A inhibitors using a structurebased virtual screening method followed by biochemical and in vitro validation. Over twenty million chemical compounds from the ZINC database were used for docking studies. The precision of the calculations was increased by an induced-fit docking protocol and the molecular mechanics/generalized Born surface area (MM/GBSA) method, which yielded approximate values for the binding energy of the protein-ligand complex. After clustering and ranking their activity, the top-ranking compounds were tested against PP2C group A members in vitro and their in vivo activity was also explored. Phosphatase activity assays identified two compounds with significant inhibitory activity against ABI1 protein ranging from around 57 to 91% at a concentration of 100 mM. Importantly, this in vitro activity correlated well with in vivo inhibition of seed germination, as expected for PP2C inhibitors. The results should promote the design of novel inhibitors with improved potency against ABI1-like and other PP2Cs that might be used in agriculture for the protection of crops against stress.

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“…Thus, a genetic approach to reduce plant transpiration includes the overexpression of ABA receptors (6,26,(38)(39)(40)(41) or the reduced expression of the PP2C co-receptors (6,35,42). In addition, there is an emerging field for the development of chemical compounds that act as ABA receptor agonists (37,(43)(44)(45)(46)(47)(48) or antagonists (49)(50)(51) to modulate ABA signaling dynamically and exogenously. The chemical approach might specifically target those ABA receptors involved in regulation of plant transpiration, root water uptake, and hydrotropism (5,6).…”

Section: Introductionmentioning

confidence: 99%

Structure-guided engineering of a receptor-agonist pair for inducible activation of the ABA adaptive response to drought

et al. 2023

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Strategies to activate abscisic acid (ABA) receptors and boost ABA signaling by small molecules that act as ABA receptor agonists are promising biotechnological tools to enhance plant drought tolerance. Protein structures of crop ABA receptors might require modifications to improve recognition of chemical ligands, which in turn can be optimized by structural information. Through structure-based targeted design, we have combined chemical and genetic approaches to generate an ABA receptor agonist molecule (iSB09) and engineer a CsPYL1 ABA receptor, named CsPYL1 5m , which efficiently binds iSB09. This optimized receptor-agonist pair leads to activation of ABA signaling and marked drought tolerance. No constitutive activation of ABA signaling and hence growth penalty was observed in transformed Arabidopsis thaliana plants. Therefore, conditional and efficient activation of ABA signaling was achieved through a chemical-genetic orthogonal approach based on iterative cycles of ligand and receptor optimization driven by the structure of ternary receptor-ligand-phosphatase complexes.

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Drug Discovery for Thirsty Crops

Cited by 12 publications

References 11 publications

Synthesis and Exploration of Abscisic Acid Receptor Agonists Against Dought Stress by Adding Constraint to a Tetrahydroquinoline‐Based Lead Structure

Synthesis and Exploration of Abscisic Acid Receptor Agonists Against Dought Stress by Adding Constraint to a Tetrahydroquinoline‐Based Lead Structure

Identification of Novel Inhibitors of a Plant Group A Protein Phosphatase Type 2C Using a Combined In Silico and Biochemical Approach

Structure-guided engineering of a receptor-agonist pair for inducible activation of the ABA adaptive response to drought

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