Covalent enzyme inhibitors have garnered renewed interest in the past few years, largely stemming from the potency and selectivity advantages that covalent drugs have over non-covalent approaches. Recently, our group has discovered that fragment-sized 4-halopyridines can modify the active site cysteine of dimethylarginine dimethylaminohydrolase (DDAH-1), an enzyme critical for nitric oxide signaling. Follow-up studies have shown that halopyridines are largely inert towards free thiols, but can be modified in the specific microenvironment found in the DDAH-1 active site. Since this initial discovery, we have sought to derivatize halopyridines for a variety of applications, including attempts to enhance inhibitory properties and efforts to discover other targets for the halopyridine fragment. Herein, we will disclose the results of two key derivatization projects: 1) the synthesis and inhibitory constants of several amino acid-based halopyridines, and 2) the synthesis and proteomic impact of a structurally complex halopyridine probe. Undergraduate involvement in each project will be emphasized.

Derivatization of halopyridines for covalent enzyme inhibition

254th National Meeting (2017)

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