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Discovery of a small-molecule inhibitor of the TRIP8b-HCN interaction with
efficacy in neurons.
Authors Han Y, Iyamu ID, Clutter MR, Mishra RK, Lyman KA, Zhou C, Michailidis I, Xia MY,
Sharma H, Luan CH, Schiltz GE, Chetkovich DM
Submitted By Submitted Externally on 10/5/2022
Status Published
Journal The Journal of biological chemistry
Year 2022
Date Published 7/1/2022
Volume : Pages 298 : 102069
PubMed Reference 35623388
Abstract 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.


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