Department of Army Occupational Disease, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University , Chongqing, People's Republic of China.
Expert Opin Ther Targets. 2020 Jul;24(7):707-717. doi: 10.1080/14728222.2020.1758667. Epub 2020 Apr 28.
Adenosine 2A receptor (AR) is involved in many physiological and pathological functions and serves as an important drug target. Inhibition of AR may alleviate symptoms associated with a variety of neuropsychiatric disorders. However, the currently used AR antagonists have specificity limitations.
A Fab fragment (Fab2838) of an AR mouse monoclonal antibody can specifically bind to AR to form a complex and inhibit the activity of its receptor. We constructed the vector AntiAR, a small-molecule peptide that binds to and inhibits AR based on Fab2838.
Experiments in HEK293T cells showed that peptide AntiAR of 29 peptides was the most effective among the synthesized peptides in inhibiting the AR downstream signal cAMP/PKA/CREB. In neurons, the AntiAR reversed the calcium flow change induced by the AR agonist CGS21680 (1 μM). Furthermore, AntiAR expression in the mice striatum weakened the p-PKA/p-CREB signal, enhanced locomotor abilities and increased time spent in the center area in the home-cage observation experiment and increased anxiolytic behavior in the elevated-plus maze test.
Antagonistic peptide AntiAR can effectively block the AR signaling pathway. This provides a new strategy for the specific inhibition of AR and provides information needed for drug development.
腺苷 2A 受体（AR）参与多种生理和病理功能，是重要的药物靶点。抑制 AR 可能会缓解与多种神经精神疾病相关的症状。然而，目前使用的 AR 拮抗剂具有特异性限制。
一种 AR 小鼠单克隆抗体的 Fab 片段（Fab2838）可以特异性结合 AR 形成复合物并抑制其受体的活性。我们构建了载体 AntiAR，这是一种基于 Fab2838 与 AR 结合并抑制其活性的小分子肽。
在 HEK293T 细胞中的实验表明，在所合成的肽中，29 肽的肽 AntiAR 是抑制 AR 下游信号 cAMP/PKA/CREB 最有效的肽。在神经元中，AntiAR 逆转了 AR 激动剂 CGS21680（1 μM）诱导的钙流变化。此外，AntiAR 在小鼠纹状体中的表达减弱了 p-PKA/p-CREB 信号，增强了在自主笼观察实验中的运动能力和在中央区域的停留时间，并增加了高架十字迷宫测试中的焦虑样行为。
拮抗肽 AntiAR 可以有效阻断 AR 信号通路。这为 AR 的特异性抑制提供了新策略，并为药物开发提供了所需的信息。
