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

Ye Han; Iredia D Iyamu; Matthew R Clutter; Rama K Mishra; Kyle A Lyman; Chengwen Zhou; Ioannis Michailidis; Maya Y Xia; Horrick Sharma; Chi-Hao Luan; Gary E Schiltz; Dane M Chetkovich

doi:10.1016/j.jbc.2022.102069

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

J Biol Chem. 2022 Jul;298(7):102069. doi: 10.1016/j.jbc.2022.102069. Epub 2022 May 24.

Authors

Affiliations

¹ Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, USA.
³ High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
⁴ Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA.
⁵ Department of Neurology, Stanford University, Palo Alto, California, USA.
⁶ 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.
⁷ 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: [email protected].
⁸ Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address: [email protected].

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.

Keywords: HCN; I(h); TRIP8b; h current; hippocampus; major depressive disorder; small molecule.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cyclic Nucleotide-Gated Cation Channels / metabolism
Depressive Disorder, Major* / metabolism
Hippocampus / metabolism
Humans
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
Mammals / metabolism
Neurons / metabolism

Substances

Cyclic Nucleotide-Gated Cation Channels
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

Abstract

Publication types

MeSH terms

Substances

Grants and funding