Discovery of a small-molecule inhibitor of the TRIP8b-HCN interaction with efficacy in neurons.

Autor:	Han Y; Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Iyamu ID; Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, USA., Clutter MR; High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA., Mishra RK; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA., Lyman KA; Department of Neurology, Stanford University, Palo Alto, California, USA., Zhou C; Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Michailidis I; Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Xia MY; Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Sharma H; Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, USA., Luan CH; High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Schiltz GE; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Pharmacology, Northwestern University, Chicago, Illinois, USA; Department of Chemistry, Northwestern University, Evanston, Illinois, USA. Electronic address: gary-schiltz@northwestern.edu., Chetkovich DM; Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address: dane.m.chetkovich@vumc.org.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Jul; Vol. 298 (7), pp. 102069. Date of Electronic Publication: 2022 May 24.
DOI:	10.1016/j.jbc.2022.102069
Abstrakt:	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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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