In Search of Small Molecules That Selectively Inhibit MBOAT4

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-12, Vol.26 (24), p.7599
• Main Authors: Murzinski, Emily S, Saha, Ishika, Ding, Hui, Strugatsky, David, Hollibaugh, Ryan A, Liu, Haixia, Tontonoz, Peter, Harran, Patrick G
• Format: Article
• Language: English
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - chemistry; Acyltransferases - metabolism; Amino acids; Animals; Binding sites; Cell culture; Coenzyme A; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzymes; Food intake; Gastric Mucosa - enzymology; Ghrelin; Ghrelin - metabolism; ghrelin O-acyl transferase; Glucose; Homeostasis; Insulin; Insulin secretion; Lipoylation; MBOAT 4; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Mice; Mucosa; Pancreas; Peptides; peptidomimetic; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Permeability; Pharmacokinetics; Pituitary; Post-translation; Residues; Secretion
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26247599

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 -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.