Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors
Identification of Small-Molecule Positive Modulators of Calcitonin-like Receptor-Based Receptors
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DOI：
10.1021/acsptsci.9b00108
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发表时间：
2020-04-10
影响因子：
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通讯作者：
Hay, Debbie L.
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文献类型：
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作者：
Hendrikse, Erica R.;Liew, Lydia P.;Hay, Debbie L.
B、G类蛋白偶联受体在治疗上具有很高的相关性，但在寻找合适的小分子药物方面仍然存在挑战。降钙素样受体(CLR)尤其与偏头痛、心血管疾病和炎症性肠病等疾病有关。CLR不能单独作为细胞表面受体，而必须与三种受体活性修饰蛋白(RAMP)中的一种偶联，形成肾上腺髓质素和降钙素基因相关肽的异二聚体受体。这些多肽在它们的受体上扩展了结合部位。这就是为什么很少有小分子配体可以调节这些受体的原因之一。在这里，我们描述了能够通过所有三个RAMP正向调节CLR信号的小分子，但在相关的降钙素受体上不活跃。这些化合物是从β-arrestin招募筛选中挑选出来的，并结合了几轮药物化学来提高它们的活性。在血管细胞系模型中，这些化合物可以正向调节cAMP信号，从而显示出翻译潜力。结合实验不支持胞外结构域结合位点；然而，分子模拟揭示了多个受体区域中潜在的变构结合位点。这是为CLR：RAMP络合物描述的第一个小分子正调制器。
Class B G protein-coupled receptors are highly therapeutically relevant but challenges remain in identifying suitable small-molecule drugs. The calcitonin-like receptor (CLR) in particular is linked to conditions such as migraine, cardiovascular disease, and inflammatory bowel disease. The CLR cannot act as a cell-surface receptor alone but rather must couple to one of three receptor activity-modifying proteins (RAMPs), forming heterodimeric receptors for the peptides adrenomedullin and calcitonin gene-related peptide. These peptides have extended binding sites across their receptors. This is one reason why there are few small-molecule ligands that can modulate these receptors. Here we describe small molecules that are able to positively modulate the signaling of the CLR with all three RAMPs but are not active at the related calcitonin receptor. These compounds were selected from a beta-arrestin recruitment screen, coupled with rounds of medicinal chemistry to improve their activity. Translational potential is shown as the compounds can positively modulate cAMP signaling in a vascular cell line model. Binding experiments do not support an extracellular domain binding site; however, molecular modeling reveals potential allosteric binding sites in multiple receptor regions. These are the first small-molecule positive modulators described for the CLR:RAMP complexes.