Target identification strategies in plant chemical biology

Abstract

The current needs to understand gene function in plant biology increasingly require more dynamic and conditional approaches opposed to classic genetic strategies. Gene redundancy and lethality can substantially complicate research, which might be solved by applying a chemical genetics approach. Now understood as the study of small molecules and their effect on biological systems with subsequent target identification, chemical genetics is a fast developing field with a strong history in pharmaceutical research and drug discovery. In plant biology however, chemical genetics is still largely in the starting blocks, with most studies relying on forward genetics and phenotypic analysis for target identification, whereas studies including direct target identification are limited. Here, we provide an overview of recent advances in chemical genetics in plant biology with a focus on target identification. Furthermore, we discuss different strategies for direct target identification and the possibilities and challenges for plant biology.

Chemical Genetics Uncovers Novel Inhibitors of Lignification, Including p-Iodobenzoic Acid Targeting CINNAMATE-4-HYDROXYLASE

“…Finally, compounds can be applied easily to essentially any plant model system or crop, whereas a genetic perturbation needs to be introduced in one genotype at a time (Tóth and van der Hoorn, 2010). Thanks to these characteristics, chemical biology has been successful for drug discovery (Cong et al, 2012), and it is becoming increasingly more popular to discover molecular mechanisms of physiological processes in plants (De Rybel et al, 2009Dejonghe and Russinova, 2014;Hicks and Raikhel, 2014).…”

Plant Chemical Genetics: From Phenotype-Based Screens to Synthetic Biology

“…A serious disadvantage in plant chemical genetics is the lack of implementation of robust MoA technologies, as in the drug discovery field (Wagner and Schreiber, 2016). Most target identification strategies in plant chemical genetics adopt a candidate approach or screening for compound-resistant mutants (Tresch, 2013;Dejonghe and Russinova, 2014). Although screening for compound-resistant mutants often is the preferred strategy, surprisingly, thus far, the most successful target identification has been obtained with the candidate approach.…”

“…This method often is used in drug discovery (Ziegler et al, 2013), but is less popular in plant chemical genetics (Dejonghe and Russinova, 2014). One of the few recent examples of affinity-based target identification in plant chemical biology was obtained from the ES2 MoA study, in which a biotin-tagged ES2 analog was used to identify EXO70 as an ES2 target (Zhang et al, 2016).…”

“…One commonly employed method to identify candidate targets is screening, in which a mutagenized plant population, for instance, is monitored for resistance against the selected small molecule. Over the years, other target identification approaches have been adopted, including affinity purification, but the plant field still lags behind the drug discovery field in expertise and applications (Ziegler et al, 2013;Dejonghe and Russinova, 2014). Here, our aim is to provide an overview of the recent progress in plant chemical genetics, including details regarding the tools and approaches used as well as the biological questions addressed and the insights gained.…”

“…The discovery of penicillin in 1928 marked the onset of an era of increasing ability to utilize, design, and repurpose small molecules to alter biological processes. Well-known examples are medicinal drugs and various herbicides and fungicides, but in the last decade, small molecules have become valuable tools in basic plant research (Surpin and Raikhel, 2004;Raikhel, 2009, 2010;Tresch, 2013;Dejonghe and Russinova, 2014;Serrano et al, 2015). Especially, the potential to overcome the obstacles of gene essentiality or high redundancy in gene families has made chemical genetics an attractive alternative to classical genetics approaches.…”