Drug Discovery Biology and Department of Pharmacology and Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4614-9. doi: 10.1073/pnas.1320962111. Epub 2014 Mar 11.
The concepts of allosteric modulation and biased agonism are revolutionizing modern approaches to drug discovery, particularly in the field of G protein-coupled receptors (GPCRs). Both phenomena exploit topographically distinct binding sites to promote unique GPCR conformations that can lead to different patterns of cellular responsiveness. The adenosine A1 GPCR (A1AR) is a major therapeutic target for cardioprotection, but current agents acting on the receptor are clinically limited for this indication because of on-target bradycardia as a serious adverse effect. In the current study, we have rationally designed a novel A1AR ligand (VCP746)--a hybrid molecule comprising adenosine linked to a positive allosteric modulator--specifically to engender biased signaling at the A1AR. We validate that the interaction of VCP746 with the A1AR is consistent with a bitopic mode of receptor engagement (i.e., concomitant association with orthosteric and allosteric sites) and that the compound displays biased agonism relative to prototypical A1AR ligands. Importantly, we also show that the unique pharmacology of VCP746 is (patho)physiologically relevant, because the compound protects against ischemic insult in native A1AR-expressing cardiomyoblasts and cardiomyocytes but does not affect rat atrial heart rate. Thus, this study provides proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.
变构调节和偏向激动作用的概念正在彻底改变现代药物发现方法，特别是在 G 蛋白偶联受体（GPCR）领域。这两种现象都利用了不同的拓扑结合位点来促进独特的 GPCR 构象，从而导致不同的细胞反应模式。腺苷 A1 GPCR（A1AR）是心脏保护的主要治疗靶点，但目前针对该受体的药物在临床上受到限制，因为作为一种严重的不良反应，其靶点为心动过缓。在本研究中，我们合理设计了一种新型 A1AR 配体（VCP746）--一种由腺苷连接到正变构调节剂的杂交分子--专门在 A1AR 上产生偏向信号。我们验证了 VCP746 与 A1AR 的相互作用符合受体结合的双位模式（即同时与正位和变构位结合），并且该化合物相对于典型的 A1AR 配体表现出偏向激动作用。重要的是，我们还表明，VCP746 的独特药理学在（病理）生理学上是相关的，因为该化合物可防止在原代表达 A1AR 的心肌细胞和心肌细胞中发生缺血性损伤，但不影响大鼠心房心率。因此，本研究提供了一个概念验证，即双位配体可以被设计为偏向激动剂，以在不产生靶点副作用的情况下提高靶点疗效。
