Ghrelin is a secreted peptide hormone involved in the regulation of multiple physiological processes including appetite, glucose metabolism, and neurological responses to stress. Ghrelin requires a unique serine octanoylation posttranslational modification to bind and activate its cognate receptor, with this modification catalyzed by ghrelin <i>O</i>-acyltransferase (GOAT). Inhibition of ghrelin acylation by GOAT could provide new avenues for treating health conditions impacted by ghrelin signaling. This will require development of potent and specific GOAT inhibitors, which will be aided by a molecular-level understanding of GOAT’s structure and catalytic architecture. Towards this goal, novel irreversible GOAT inhibitors were designed and synthesized to aid in the identification of active site residues, substrate binding sites, and inhibitor binding sites within GOAT. In the search for irreversible modifiers of GOAT, cysteine-reactive small molecules were synthesized and tested for inhibition of GOAT. Furthermore, known inhibitors of GOAT were altered to contain moieties designed to create irreversible covalent modification of the enzyme. Development of these compounds will increase the chemical options for targeting GOAT and enable the labeling and characterization of the GOAT active site. We will describe our synthetic and biochemical progress towards new GOAT inhibitors as tools for both enzymology and further GOAT inhibitor development.

Synthesis and development of small-molecule probes targeting ghrelin <i>O</i>-acyltransferase

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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Synthesis and development of small-molecule probes targeting ghrelin O-acyltransferase