比利时布鲁塞尔自由大学Steven Ballet团队提出了应用于药物开发中能够稳定活性状态Gs蛋白偶联受体的G蛋白肽类仿制药的开发。 相关研究成果于2021年2月17日发表在国际顶尖学术期刊《德国应用化学》。

G蛋白偶联受体（GPCRs）是一类重要的膜蛋白，在现代医学中起着核心作用。不幸的是，构象混乱阻碍了GPCRs的充分治疗利用，因为受体的最大群体将采用基本构象，因此对兴奋剂药物发现项目提出了挑战。

该文中，研究人员描述了一组能够模拟G蛋白稳定β2肾上腺素受体（β2AR）和多巴胺1受体（D1R）活性状态的拟肽。在基于片段的筛选工作中，这些（不受约束的）G s蛋白中α5螺旋的限制性肽类似物能够识别所检测的GPCR的兴奋预印记片段，因此，它们作为一种通用工具，能够用于兴奋剂专用的发现项目。

附：英文原文

Title: Development of Generic G Protein Peptidomimetics Able to Stabilize Active State Gs Protein‐Coupled Receptors for Application in Drug Discovery

Author: Morgane Mannes, Charlotte Martin, Sarah Triest, Marilisa Pia Dimmito, Adriano Mollica, Toon Laeremans, Christel J. Menet, Steven Ballet

Issue&Volume: 2021-02-17

Abstract: G protein‐coupled receptors (GPCRs) represent an important group of membrane proteins that play a central role in modern medicine. Unfortunately, conformational promiscuity hampers full therapeutic exploitation of GPCRs, since the largest population of the receptor will adopt a basal conformation, which subsequently challenges screens for agonist drug discovery programs. Here, we describe a set of peptidomimetics able to mimic the ability of G proteins in stabilizing the active state of the β  2  adrenergic receptor (β  2  AR) and the dopamine 1 receptor (D1R). During fragment‐based screening efforts, these (un)constrained peptide analogues of the α  5  helix in G  s  proteins, were able to identify agonism pre‐imprinted fragments for the examined GPCRs, and as such, they behave as a generic tool, enabling an engagement in agonist earmarked discovery programs.

DOI: 10.1002/anie.202100180

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202100180