Design, synthesis and evaluation of unnatural peptides as T1R2/T1R3 PAMs

Kei Yamada; Ryo Matsumoto; Yumiko Suzuki; Suguru Mori; Seiji Kitajima

doi:10.1016/j.bmcl.2020.127000

Design, synthesis and evaluation of unnatural peptides as T1R2/T1R3 PAMs

Bioorg Med Chem Lett. 2020 Apr 15;30(8):127000. doi: 10.1016/j.bmcl.2020.127000. Epub 2020 Jan 27.

Authors

Kei Yamada¹, Ryo Matsumoto², Yumiko Suzuki², Suguru Mori², Seiji Kitajima²

Affiliations

¹ Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki-Ku, Kawasaki-Shi 210-8681, Japan. Electronic address: kei_yamada@ajinomoto.com.
² Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki-Ku, Kawasaki-Shi 210-8681, Japan.

PMID: 32063432
DOI: 10.1016/j.bmcl.2020.127000

Abstract

The sweet receptor T1R2/T1R3 is a member of G protein-coupled receptor family and recognizes diverse natural and synthetic sweeteners. Previously, we reported a novel class of positive allosteric modulators (PAMs) of T1R2/T1R3 comprising an unnatural tripeptide structure. We classified the structure of these PAMs into three parts: "head", "linker" and "tail". Here, we report the design, synthesis and evaluation of various tail structures to obtain highly active unnatural peptide structure of PAM. In conclusion, we discovered the novel unnatural tetrapeptide with highly potent PAM activity on T1R2/T1R3 in a cell-based assay system.

Keywords: Enhancer; G protein-coupled receptor; PAM; T1R2/T1R3; Unnatural peptide.

MeSH terms

Allosteric Regulation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Peptides / chemical synthesis
Peptides / chemistry
Peptides / pharmacology*
Receptors, G-Protein-Coupled / metabolism*
Structure-Activity Relationship

Substances

Peptides
Receptors, G-Protein-Coupled