Development of Potent and Selective Agonists for Complement C5a Receptor 1 with In Vivo Activity,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Development of Potent and Selective Agonists for Complement C5a Receptor 1 with In Vivo Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-11 , DOI: 10.1021/acs.jmedchem.1c01174
Declan M Gorman ₁ , Xaria X Li ₁ , John D Lee ₁ , Jenny N Fung ₁ , Cedric S Cui ₁ , Han Siean Lee ₁ , Barbara E Rolfe ₂ , Trent M Woodruff _{1,

3} , Richard J Clark ₁

Affiliation

The anaphylatoxin C5a is a complement peptide associated with immune-related disorders. C5a binds with equal potency to two GPCRs, C5aR1 and C5aR2. Multiple C5a peptide agonists have been developed to interrogate the C5a receptor function but none show selectivity for C5aR1. To address these limitations, we developed potent and stable peptide C5aR1 agonists that display no C5aR2 activity and over 1000-fold selectivity for C5aR1 over C3aR. This includes BM213, which induces C5aR1-mediated calcium mobilization and pERK1/2 signaling but not β-arrestin recruitment, and BM221, which exhibits no signaling bias. Both ligands are functionally similar to C5a in human macrophage cytokine release assays and in a murine in vivo neutrophil mobilization assay. BM213 showed antitumor activity in a mouse model of mammary carcinoma. We anticipate that these C5aR1-selective agonists will be useful research tools to investigate C5aR1 function.

中文翻译：

开发具有体内活性的补体 C5a 受体 1 的强效和选择性激动剂

过敏毒素 C5a 是一种与免疫相关疾病相关的补体肽。C5a 与两个 GPCR，C5aR1 和 C5aR2 结合的效力相同。已经开发了多种 C5a 肽激动剂来询问 C5a 受体功能，但没有一种显示对 C5aR1 的选择性。为了解决这些限制，我们开发了有效且稳定的肽 C5aR1 激动剂，它们不显示 C5aR2 活性，并且对 C5aR1 的选择性比 C3aR 高 1000 倍以上。这包括 BM213，它诱导 C5aR1 介导的钙动员和 pERK1/2 信号传导，但不诱导 β-arrestin 募集，以及 BM221，它没有表现出信号偏差。在人巨噬细胞细胞因子释放试验和鼠体内中性粒细胞动员试验中，这两种配体在功能上与 C5a 相似。BM213 在乳腺癌小鼠模型中显示出抗肿瘤活性。

更新日期：2021-11-25

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南