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

doi:10.3390/molecules26247599

Molecules (Dec 2021)

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

Affiliations

Emily S. Murzinski: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90024, USA
Ishika Saha: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90024, USA
Hui Ding: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90024, USA
David Strugatsky: Department of Microbiology, Immunology & Molecular Genetics, California and Nano Systems Institute, University of California, Los Angeles, CA 90024, USA
Ryan A. Hollibaugh: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90024, USA
Haixia Liu: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90024, USA
Peter Tontonoz: Department of Biological Chemistry, University of California, Los Angeles, CA 90024, USA
Patrick G. Harran: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90024, USA

DOI: https://doi.org/10.3390/molecules26247599
Journal volume & issue: Vol. 26, no. 24
p. 7599

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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