A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification

Whitney M Nolte; Jean-Philippe Fortin; Benjamin D Stevens; Gary E Aspnes; David A Griffith; Lise R Hoth; Roger B Ruggeri; Alan M Mathiowetz; Chris Limberakis; David Hepworth; Philip A Carpino

doi:10.1038/nchembio.1581

A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification

Nat Chem Biol. 2014 Aug;10(8):629-31. doi: 10.1038/nchembio.1581. Epub 2014 Jul 6.

Affiliations

¹ Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
² Cardiovascular and Metabolic Diseases Research Unit, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
³ Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.
⁴ Structural Biology and Biophysics Group, Center for Chemistry Innovation and Excellence, Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.

PMID: 24997604
DOI: 10.1038/nchembio.1581

Abstract

We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro-3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.

MeSH terms

Animals
CHO Cells
Cricetulus
Cysteine / chemistry
Glucagon-Like Peptide 1 / agonists
Glucagon-Like Peptide-1 Receptor
Humans
Ligands
Pyrimidines / chemistry*
Pyrimidines / metabolism
Receptors, Glucagon / chemistry
Receptors, Glucagon / metabolism*

Substances

4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine
GLP1R protein, human
Glucagon-Like Peptide-1 Receptor
Ligands
Pyrimidines
Receptors, Glucagon
Glucagon-Like Peptide 1
Cysteine

Associated data

PubChem-Substance/183814150
PubChem-Substance/183814151
PubChem-Substance/183814152
PubChem-Substance/183814153
PubChem-Substance/183814154