In Search of Small Molecules That Selectively Inhibit MBOAT4.

Emily S Murzinski, Ishika Saha, Hui Ding, David Strugatsky, Ryan A Hollibaugh, Haixia Liu, Peter Tontonoz, Patrick G Harran

Molecules (Basel, Switzerland) 2021 Dec 15

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Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site.

Citation

Emily S Murzinski, Ishika Saha, Hui Ding, David Strugatsky, Ryan A Hollibaugh, Haixia Liu, Peter Tontonoz, Patrick G Harran. In Search of Small Molecules That Selectively Inhibit MBOAT4. Molecules (Basel, Switzerland). 2021 Dec 15;26(24)