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In Search of Small Molecules That Selectively Inhibit MBOAT4

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 ta...

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Autores principales: Murzinski, Emily S., Saha, Ishika, Ding, Hui, Strugatsky, David, Hollibaugh, Ryan A., Liu, Haixia, Tontonoz, Peter, Harran, Patrick G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709388/
https://www.ncbi.nlm.nih.gov/pubmed/34946685
http://dx.doi.org/10.3390/molecules26247599
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author Murzinski, Emily S.
Saha, Ishika
Ding, Hui
Strugatsky, David
Hollibaugh, Ryan A.
Liu, Haixia
Tontonoz, Peter
Harran, Patrick G.
author_facet Murzinski, Emily S.
Saha, Ishika
Ding, Hui
Strugatsky, David
Hollibaugh, Ryan A.
Liu, Haixia
Tontonoz, Peter
Harran, Patrick G.
author_sort Murzinski, Emily S.
collection PubMed
description 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.
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spelling pubmed-87093882021-12-25 In Search of Small Molecules That Selectively Inhibit MBOAT4 Murzinski, Emily S. Saha, Ishika Ding, Hui Strugatsky, David Hollibaugh, Ryan A. Liu, Haixia Tontonoz, Peter Harran, Patrick G. Molecules Article 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. MDPI 2021-12-15 /pmc/articles/PMC8709388/ /pubmed/34946685 http://dx.doi.org/10.3390/molecules26247599 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Murzinski, Emily S.
Saha, Ishika
Ding, Hui
Strugatsky, David
Hollibaugh, Ryan A.
Liu, Haixia
Tontonoz, Peter
Harran, Patrick G.
In Search of Small Molecules That Selectively Inhibit MBOAT4
title In Search of Small Molecules That Selectively Inhibit MBOAT4
title_full In Search of Small Molecules That Selectively Inhibit MBOAT4
title_fullStr In Search of Small Molecules That Selectively Inhibit MBOAT4
title_full_unstemmed In Search of Small Molecules That Selectively Inhibit MBOAT4
title_short In Search of Small Molecules That Selectively Inhibit MBOAT4
title_sort in search of small molecules that selectively inhibit mboat4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709388/
https://www.ncbi.nlm.nih.gov/pubmed/34946685
http://dx.doi.org/10.3390/molecules26247599
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