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
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.
