A formidable challenge in the genomic era is the assignment of structure and function to unknown genes in model organisms. Forward chemical genetics seeks to discover and characterize pathways through the identification of novel phenotypes induced by organic small molecules and subsequent isolation of their target gene(s). Downstream genetic and biochemical strategies to dissect the action of bioactive molecules can be hampered by weak target-ligand interactions, low target abundance, genetic factors, and synthetic inaccessibility of analogs. We designed a synthetic scaffold that simultaneously permits fluorescence detection (dansyl) and photoaffinity labeling (diazirine) in a combinatorial library of thousands of drug-like small molecules synthesized through click chemistry. Using this library, we identified several bioactives in Arabidopsis thaliana and generated EMS-induced resistant mutants for SSLP marker-assisted mapping and downstream SNP identification by Illumina sequencing. Our proof-of-principle study will facilitate target identification of novel bioactives and accelerate future chemical genetics based discoveries.

Forward chemical genetics in Arabidopsis: Synthesis and characterization of bioactive fluorescent small molecules containing photoaffinity labels

243rd National Meeting (2012)

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