A modular approach to triazole-containing chemical inducers of dimerisation for yeast three-hybrid screening.
The yeast three-hybrid (Y3H) approach shows considerable promise for the unbiased identification of novel small molecule-protein interactions. In recent years, it has been successfully used to link a number of bioactive molecules to novel protein binding partners. However despite its potential importance as a protein target identification method, the Y3H technique has not yet been widely adopted, in part due to the challenges associated with the synthesis of the complex chemical inducers of dimerisation (CIDs). The development of a modular approach using potentially "off the shelf" synthetic components was achieved and allowed the synthesis of a family of four triazole-containing CIDs, MTX-Cmpd2.2-2.5. These CIDs were then compared using the Y3H approach with three of them giving a strong positive interaction with a known target of compound 2, TgCDPK1. These results showed that the modular nature of our synthetic strategy may help to overcome the challenges currently encountered with CID synthesis and should contribute to the Y3H approach reaching its full potential as an unbiased target identification strategy.
School of Chemistry and Biomolecular Sciences Research Complex, University of St Andrews and EaStCHEM, North Haugh, St Andrews, Fife, Scotland KY16 9ST, UK. gward@uvm.edu.
Fanny
F
Tran
Anahi V
AV
Odell
Gary E
GE
Ward
Nicholas J
NJ
Westwood
D057930:Click Chemistry; D004353:Drug Evaluation, Preclinical; D011494:Protein Kinases / Q000096:biosynthesis; D055503:Protein Multimerization / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014122:Toxoplasma / Q000201:enzymology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D015003:Yeasts / Q000378:metabolism
D011993:Recombinant Fusion Proteins; D014230:Triazoles; D011494:Protein Kinases