2. Academic Validation
  3. Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

  • ACS Chem Biol. 2021 Nov 19;16(11):2444-2452. doi: 10.1021/acschembio.1c00552.
Jiang Wang 1 2 3,  Dehua Yang 1,  Xi Cheng 1 3,  Linlin Yang 4,  Zhaohui Wang 1,  Antao Dai 1,  Xiaoqing Cai 1,  Chao Zhang 5,  Elita Yuliantie 1,  Qiaofeng Liu 6,  Hualiang Jiang 1 2 3,  Hong Liu 1 2 3,  Ming-Wei Wang 1 2 7,  Huaiyu Yang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 6 School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 7 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 8 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
PMID: 34570476 DOI: 10.1021/acschembio.1c00552
Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.

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