Rising temperatures and lessening fresh water supplies are two forms of environmental stress, also called abiotic stress, that lower the amount of food produced by agriculture. A key regulator of abiotic stress tolerance is the plant hormone abscisic acid (ABA), which is synthesized by plants in response to various abiotic stresses and orchestrates adaptive responses that enhance plant survival (Cutler, S. et al., Annual Review of Plant Biology (2010); Nambara, E. et al., Annual Review of Plant Biology 56:165-185 (2005)). Crop plants engineered to have increased ABA sensitivity show improved yield under conditions of drought (Wang, Y. et al., Plant J 43:413-424 (2005)). Moreover, the direct application of ABA or ABA analogs to plants in the field has been shown to improve water use efficiency (Hawkins, A. F. et al., Plant Growth Regulators for Agricultural and Amenity Use (British Crop Protection Council) (1987); Kreeb, K. H. et al., Structural and Functional Responses to Environmental Stresses (Balogh Scientific Books) (1989)); however, ABA has not been successfully commercialized for this use given its complicated production routes and high cost.
Interestingly, numerous fungicides and insecticides have shown stress-tolerance “side-effects” of unknown mechanism and have been commercialized for stress-tolerance uses, which demonstrates the strong interest in, and recognized need for chemical methods to control stress tolerance (Asrar, J. et al., In US 2009/0270254 A1 (USA, Monsanto Technology) (2003); Beckers, G. J. M. et al., Current Opinion in Plant Biology 10:425-431 (2007); Schulz, A. et al., In US 2007/0124839 A1 (USA, Bayer Crop Sciences) (2006)). An important driver of this interest has been the realization that the dramatic increases in corn yield achieved over last 100 years can be attributed largely to improvements in abiotic stress tolerance of new high-yielding corn varieties (Duvick, D. N. et al., Crop Science 39:1622-1630 (1999); Tollenaar, M. et al., Field Crops Research 75:161-169 (2002); Tollenaar, M. et al., Crop Sci 39:1597-1604 (1999)). Because ABA is recognized as the critical hormonal regulator of plant stress physiology, there is intense interest in modulating the ABA pathway in crops. One possible point at which to control the ABA signaling pathway is receptor proteins, which in principle would allow both chemical and genetic modulation of ABA signaling and stress tolerance.
Recently a new family of ABA receptors, the Pyrabactin resistance/PYR-like (“PYR/PYL”) family, was identified as a modulator of ABA signaling (Park, S. Y. et al., Science 324:1068-1071 (2009)). The over-expression of the ABA receptor PYL5 confers drought tolerance on Arabidopsis plants (Santiago, J. et al., The Plant Journal 60(4):575-578 (2009)), validating this new receptor family as a key target for control of plant stress tolerance. However, gene over-expression can have adverse yield consequences, which are referred to as “yield drag”. Yield drag is thought to occur because the unregulated activation of stress tolerance pathways, which is associated with slowed growth, occurs under normal conditions (i.e. in the absence of drought or other stressors). See, D. W., J Exp Bot 64(1): 83-108 (2013). One way to gain regulated control of ABA signaling is to develop chemical agents that activate ABA receptors (i.e. agonists). These can be applied to plants once drought or other stress conditions have ensued, which allows for selective protection in adverse conditions. This allows the benefits of stress tolerance to be realized without lowering yield under ideal growth conditions.
In principle, ABA could be used as an agonist to realize these advantages. However, it is a natural product that is costly to make and rapidly degraded by both UV photo-isomerization and metabolic inactivation. It also has physiological effects in mammals that could conceivably affect its suitability for use as an agrochemical (Guri, A. J. et al., Clin Nutr. (2010)).