An overview of ghrelin O-acyltransferase inhibitors: a literature and patent review for 2010-2019

ABSTRACT

Introduction

The peptide hormone ghrelin regulates physiological processes associated with energy homeostasis such as appetite, insulin signaling, glucose metabolism, and adiposity. Ghrelin has also been implicated in a growing number of neurological pathways involved in stress response and addiction behavior. For ghrelin to bind the growth hormone secretagogue receptor 1a (GHS-R1a) and activate signaling, the hormone must first be octanoylated on a specific serine side chain. This key transformation is performed by the enzyme ghrelin O-acyltransferase (GOAT), and therefore GOAT inhibitors may be useful in treating disorders related to ghrelin signaling such as diabetes, obesity, and related metabolic syndromes.

Areas covered

This report covers ghrelin and GOAT as potential therapeutic targets and summarizes work on GOAT inhibitors through the end of 2019, highlighting recent successes with both peptidomimetics and small molecule GOAT inhibitors as potent modulators of GOAT-catalyzed ghrelin octanoylation.

Expert opinion

A growing body of biochemical and structural knowledge regarding the ghrelin/GOAT system now enables multiple avenues for identifying and optimizing GOAT inhibitors. We are at the beginning of a new era with increased opportunities for leveraging ghrelin and GOAT in the understanding and treatment of multiple health conditions including diabetes, obesity, and addiction.

KEYWORDS:

• Ghrelin
• ghrelin O-acyltransferase
• GHS-R1a receptor
• membrane-bound O-acyltransferase
• protein acylation
• diabetes
• obesity
• metabolic syndrome
• addiction
• alcoholism

Article highlights

• Ghrelin is a peptide hormone implicated in food intake, metabolic regulation, stress response, and addictive behaviors.

• To be biologically active, ghrelin must be modified with an eight-carbon acyl group by ghrelin O-acyltransferase (GOAT).

• Development of potent peptidomimetic and small molecule GOAT inhibitors offers the opportunity to modulate ghrelin signaling by blocking GOAT acylation activity.

• GOAT inhibitors have recently entered preclinical and clinical studies.

• Ghrelin and GOAT provide potential unexploited therapeutic avenues for treating diabetes, obesity, and addiction.

Declaration of interest

JL Hougland and JD Chisholm have patent interests in GOAT inhibitors discussed in this review. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants from the National Institutes of Health [GM134102, JL Hougland and JD Chisholm]; the American Diabetes Association [1-16-JDF-042, JL Hougland]; and Syracuse University.