Abolishing β‐arrestin recruitment is necessary for the full metabolic benefits of G protein‐biased glucagon‐like peptide‐1 receptor agonists

Author:

Hinds Charlotte E.1ORCID,Peace Ellie1,Chen Shiqian1,Davies Iona1,El Eid Liliane2,Tomas Alejandra2ORCID,Tan Tricia1ORCID,Minnion James1ORCID,Jones Ben1ORCID,Bloom Stephen R.1

Affiliation:

1. Section of Endocrinology and Investigative Medicine Imperial College London London UK

2. Section of Cell Biology Imperial College London London UK

Abstract

AbstractAimEarlier studies have shown that peptide glucagon‐like peptide‐1 receptor (GLP‐1R) agonists with reduced β‐arrestin recruitment show enhanced anti‐hyperglycaemic efficacy through avoidance of GLP‐1R desensitization. However, the ligand modifications needed to decrease β‐arrestin recruitment usually also reduces GLP‐1R affinity, therefore higher doses are needed. Here we aimed to develop new, long‐acting, G protein‐biased GLP‐1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios.Materials and MethodsNew GLP‐1R agonist peptides were assessed using a variety of in vitro and in vivo assays.ResultsFirst, we show that very substantial reductions in β‐arrestin recruitment efficacy are required to realize fully the benefits of GLP‐1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist‐specific GLP‐1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP‐1R agonist pharmacogenomics.ConclusionsCompletely abolishing β‐arrestin recruitment improves the anti‐hyperglycaemic effects of GLP‐1R agonists in mice.

Funder

Diabetes UK

Medical Research Council

NIHR Imperial Biomedical Research Centre

Publisher

Wiley

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism,Internal Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3