A small molecule antagonist of ghrelin O-acyltransferase (GOAT)

Abstract

Using our recently disclosed fluorescence-based assay to monitor acyltransferase activity, the first non-peptidic, small molecule antagonists of ghrelin O-acyltransferase (GOAT), a potential anti-obesity and anti-diabetes target, have been discovered. Each exhibits micromolar inhibition of the enzyme, and may be useful probes for future study of the ghrelin-GOAT system.

A new class of ghrelin O-acyltransferase inhibitors incorporating triazole-linked lipid mimetic groups

“…22,29 This substrate incorporates the N-terminal sequence elements shown to be essential for ghrelin recognition by hGOAT, 20,22,48 and has exhibited comparable behavior in GOAT inhibitor studies as compared to other assays using proghrelin or other ghrelin-derived peptides. 20,26,27 In initial screening of unpurified inhibitors at 0.1 and 1 lM concentrations, the inhibitor bearing the phenylpropyl triazole group (8d) exhibited the largest degree of inhibition (Fig. S1).…”

“…This inhibition demonstrated that hGOAT can accept the triazole group in place of an ester or amide linkage, and that the acyl binding pocket within the hGOAT active site can accommodate a bulky aromatic group in place of a linear alkyl group present in previously reported GOAT inhibitors. 20,25,27 To define the structure-activity relationship for the phenylalkyl triazole inhibitor series, we synthesized and purified inhibitors bearing alkyl chains from one to four carbons connecting the triazole and phenyl rings (8b-e, Fig. 2).…”

“…Several groups have reported examples of GOAT inhibitors based on either mimics of ghrelin/acylated ghrelin, screening of small molecule libraries, or bisubstrate molecules incorporating features of the ghrelin and octanoyl-coenzyme A substrates. 20,[25][26][27] The peptidebased bisubstrate inhibitor GO-CoA-Tat developed by Cole and coworkers effectively inhibited GOAT in both cultured mammalian cells and mice, and treatment of mice with this inhibitor increased glucose tolerance and reduced weight gain. 25 However, none of the currently available inhibitors are considered suitable for exploring GOAT inhibition as a means for treating human diseases due to low potency, biostability, or other factors.…”

“…22,28,29 A predominant and constant feature among the small pool of reported hGOAT inhibitors is incorporation of an amide-linked lipid group to mimic the octanoyl moiety of acylated ghrelin. 20,[25][26][27] Structure-activity studies have highlighted the importance of the lipid group in product-mimetic inhibitors for potency in inhibiting hGOAT. 20,22 To develop a strategy for creating novel hGOAT inhibitors, we focused on replacing the amide bond linkage to the lipid chain in established GOAT inhibitors with a 1,2,3-triazole linkage.…”

Ghrelin O-acyltransferase (GOAT) and energy metabolism

“…In 2011, Garner's group (Garner and Janda, 2011) identified two potential non-peptide small molecule antagonists of GOAT by using an enzyme assay based on cat-ELCCA. Two compounds were discovered and named as compounds 3a and 3b; both were found to exhibit dose-dependent antagonism of GOAT.…”