Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, USA.
J Biol Chem. 2022 Jul;298(7):102069. doi: 10.1016/j.jbc.2022.102069. Epub 2022 May 24.
Major depressive disorder is a critical public health problem with a lifetime prevalence of nearly 17% in the United States. One potential therapeutic target is the interaction between hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and an auxiliary subunit of the channel named tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). HCN channels regulate neuronal excitability in the mammalian hippocampus, and recent work has established that antagonizing HCN function rescues cognitive impairment caused by chronic stress. Here, we utilize a high-throughput virtual screen to find small molecules capable of disrupting the TRIP8b-HCN interaction. We found that the hit compound NUCC-0200590 disrupts the TRIP8b-HCN interaction in vitro and in vivo. These results provide a compelling strategy for developing new small molecules capable of disrupting the TRIP8b-HCN interaction.
重度抑郁症是一个严重的公共卫生问题，在美国的终身患病率接近 17%。一个潜在的治疗靶点是超极化激活环核苷酸门控 (HCN) 通道与通道的辅助亚基之间的相互作用，该辅助亚基名为四肽重复结构域包含 Rab8b 相互作用蛋白 (TRIP8b)。HCN 通道调节哺乳动物海马体中的神经元兴奋性，最近的工作已经确定，拮抗 HCN 功能可以挽救慢性应激引起的认知障碍。在这里，我们利用高通量虚拟筛选来寻找能够破坏 TRIP8b-HCN 相互作用的小分子。我们发现，命中化合物 NUCC-0200590 可在体外和体内破坏 TRIP8b-HCN 相互作用。这些结果为开发能够破坏 TRIP8b-HCN 相互作用的新小分子提供了一种有说服力的策略。
