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Targeting G protein-coupled receptor signalling by blocking G proteins
Nature Reviews Drug Discovery ( IF 122.7 ) Pub Date : 2018-09-28 , DOI: 10.1038/nrd.2018.135
Adrian P. Campbell , Alan V. Smrcka

G protein-coupled receptors (GPCRs) are the largest class of drug targets, largely owing to their druggability, diversity and physiological efficacy. Many drugs selectively target specific subtypes of GPCRs, but high specificity for individual GPCRs may not be desirable in complex multifactorial disease states in which multiple receptors may be involved. One approach is to target G protein subunits rather than the GPCRs directly. This approach has the potential to achieve broad efficacy by blocking pathways shared by multiple GPCRs. Additionally, because many GPCRs couple to multiple G protein signalling pathways, blocking specific G protein subunits can 'bias' GPCR signals by inhibiting only a subset of these signals. Molecules that target G protein α or βγ-subunits have been developed and show strong efficacy in multiple preclinical disease models and biased inhibition of G protein signalling. In this Review, we discuss the development and characterization of G protein α and βγ-subunit ligands and the preclinical evidence that this exciting new approach has potential for therapeutic efficacy in a number of indications, such as pain, thrombosis, asthma and heart failure.



中文翻译:

通过阻断G蛋白靶向G蛋白偶联的受体信号传导

G蛋白偶联受体(GPCR)是最大的药物靶标类型,这主要是由于它们的可成药性,多样性和生理功效。许多药物选择性地靶向GPCR的特定亚型,但是在可能涉及多个受体的复杂的多因素疾病状态下,对单个GPCR的高特异性可能是不希望的。一种方法是靶向G蛋白亚基,而不是直接靶向GPCR。这种方法有可能通过阻断多个GPCR共有的途径来达到广泛的疗效。此外,由于许多GPCR耦合到多个G蛋白信号传导途径,因此阻断特定G蛋白亚基可以通过仅抑制这些信号的一部分来“偏向” GPCR信号。已开发出靶向G蛋白α或βγ亚基的分子,并在多种临床前疾病模型中以及对G蛋白信号转导的偏向抑制方面显示出强大的功效。在这篇综述中,我们讨论了G蛋白α和βγ亚基配体的开发和表征,以及临床前证据,该令人振奋的新方法在许多适应症(如疼痛,血栓形成,哮喘和心力衰竭)中具有治疗功效的潜力。

更新日期:2018-12-10
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