Chemical biology utilizes chemistry to unmask novel biological processes in living organisms. In the Buczynski lab, we use this approach to identify novel protein expression, activity, and posttranslational changes as well as screen small molecules to identify potent and selective pharmacotherapeutics that target those proteins . This technique uses chemical probes to recognize and capture proteins with a specific chemical feature of interest and tagged with either a fluorophore or biotin using click chemistry for subsequent analysis (Figure 1). Chemical biological approaches facilitate the study of distinct classes of lower abundance proteins that might not be easily detected using traditional proteomics approaches.
As a component of our work studying the role of the lipid signal 2-arachidonoylglycerol in nicotine dependence, we utilized two different chemical probes to determine the potency and selectivity of our 2-arachidonoylglycerol metabolism inhibitors in the rat proteome [2,3]. Future projects will expand on this work using chemical probes designed to evaluate protein changes resulting from chronic nicotine or alcohol exposure.
Figure 1. Schematic of a chemical biology approach for identifying protein changes in the brain.
Bachovchin DA & Cravatt BF. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat Rev Drug Discov 11, 52-68 (2012)
Buczynski MW, Herman MA, Hsu KL, Natividad LA, Irimia C, Polis IY, Pugh H, Chang JW, Niphakis MJ, Cravatt BF, Roberto M, Parsons LH. Diacylglycerol lipase disinhibits VTA DA neurons during chronic nicotine exposure. PNAS 113, 1086-91 (2016).
Niphakis MJ, Cognetta AB, Chang JW, Buczynski MW, Byrne F, Burston JJ, Chapman V, Cravatt BF. Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. ACS Chem Neurosci 4,1322-32 (2013).