小柯机器人

澳大利亚莫纳什大学Christopoulos Arthur、Wendy L. Imlach和澳大利亚沃尔特和伊丽莎·霍尔医学研究所Alisa Glukhova研究组合作取得一项新成果。经过不懈努力，他们揭示了腺苷A1受体 (A1R)调控镇痛的正变构机制。该研究于2021年9月8日发表于国际学术期刊《自然》杂志。

研究人员发现了一种新的A1R的正变构调节剂，[2-氨基-4-(3,5-双(三氟甲基)苯基)噻吩-3-基)(4-氯苯基)甲酮] (MIPS521)，其通过调节神经病理性疼痛大鼠脊髓中增加的内源性腺苷水平发挥镇痛功效。研究人员还解析了与腺苷、MIPS521 和 Gi2 异源三聚体共结合的A1R结构，揭示了一个面向脂质去垢剂的变构结合口袋，其包含跨膜螺旋1、6和7。

分子动力学模拟和配体动力学结合实验揭示了MIPS521稳定腺苷-受体-G 蛋白复合物的机制。这项研究为某些特定疾病非阿片类镇痛药物的研发提供了基于结构变构的设计思路。

据悉，A1R是非阿片类镇痛剂治疗神经性疼痛的潜在治疗靶点。然而，由于缺乏足够的靶向选择以及组织外不良反应，靶向A1R激活剂的研发并未成功。

附：英文原文

Title: Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

Author: Draper-Joyce, Christopher J., Bhola, Rebecca, Wang, Jinan, Bhattarai, Apurba, Nguyen, Anh T. N., Cowie-Kent, India, OSullivan, Kelly, Chia, Ling Yeong, Venugopal, Hariprasad, Valant, Celine, Thal, David M., Wootten, Denise, Panel, Nicolas, Carlsson, Jens, Christie, Macdonald J., White, Paul J., Scammells, Peter, May, Lauren T., Sexton, Patrick M., Danev, Radostin, Miao, Yinglong, Glukhova, Alisa, Imlach, Wendy L., Christopoulos, Arthur

Issue&Volume: 2021-09-08

Abstract: The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, MIPS521 and a Gi2 heterotrimer, revealing an extrahelical lipid–detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine–receptor–G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

DOI: 10.1038/s41586-021-03897-2

Source: https://www.nature.com/articles/s41586-021-03897-2

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