{"doi":"10.1016/j.jbc.2022.102069","title":"Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons","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. 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. Major depressive disorder (MDD) is a critical public health problem with many patients failing to respond to existing pharmacotherapies. Most antidepressants focus on monoaminergic neurotransmitters, but these drugs take several weeks to achieve their therapeutic effect and fail to treat some of the most debilitating aspects of MDD, including cognitive impairment (1Zuckerman H. Pan Z. Park C. Brietzke E. Musial N. Shariq A.S. et al.Recognition and treatment of cognitive dysfunction in major depressive disorder.Front. Psych. 2018; 9: 655Crossref PubMed Scopus (80) Google Scholar, 2Lam R.W. Kennedy S.H. McIntyre R.S. Khullar A. Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment.Can. J. Psych. 2014; 59: 649-654Crossref Scopus (207) Google Scholar). As such, there is a need for new and synergistic therapies. Cognitive impairment in MDD is often localized to the hippocampus, a key limbic structure that plays an essential role in both affect and memory. While it remains unclear how precisely stress impairs hippocampal function, many mechanisms have been described and a common endpoint is a loss of hippocampal excitability (3Campbell S. Macqueen G. The role of the hippocampus in the pathophysiology of major depression.J. Psych. Neurosci. Jpn. 2004; 29: 417-426PubMed Google Scholar). For example, chronic stress leads to a reduction in the strength of glutamatergic inputs to CA1 pyramidal neurons while monoaminergic antidepressants rescue this activity (4Cai X. Kallarackal A.J. Kvarta M.D. Goluskin S. Gaylor K. Bailey A.M. et al.Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression.Nat. Neurosci. 2013; 16: 464-472Crossref PubMed Scopus (107) Google Scholar, 5Kallarackal A.J. Kvarta M.D. Cammarata E. Jaberi L. Cai X. Bailey A.M. et al.Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses.J. Neurosci. 2013; 33: 15669-15674Crossref PubMed Scopus (123) Google Scholar, 6Dyke A.M.V. Francis T.C. Chen H. Bailey A.M. Thompson S.M. Chronic fluoxetine t","journal":"Journal of Biological Chemistry","year":2022,"id":281393,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":506173,"name":"Iredia D. Iyamu","orcid":"0000-0003-1337-1188","position":1,"is_corresponding":false},{"id":521759,"name":"Matthew R. Clutter","orcid":null,"position":2,"is_corresponding":false},{"id":280874,"name":"Rama K. Mishra","orcid":"0000-0003-3608-2602","position":3,"is_corresponding":false},{"id":499264,"name":"Kyle A. Lyman","orcid":"0000-0002-3309-7211","position":4,"is_corresponding":false},{"id":335235,"name":"Chengwen Zhou","orcid":"0000-0002-0222-1515","position":5,"is_corresponding":false},{"id":957110,"name":"Ioannis E. Michailidis","orcid":null,"position":6,"is_corresponding":false},{"id":956588,"name":"Maya Xia","orcid":"0000-0002-8853-4407","position":7,"is_corresponding":false},{"id":956589,"name":"Horrick Sharma","orcid":"0000-0002-9605-6310","position":8,"is_corresponding":false},{"id":875014,"name":"Chi‐Hao Luan","orcid":"0000-0002-2131-379X","position":9,"is_corresponding":false},{"id":242018,"name":"Gary E. Schiltz","orcid":"0000-0003-4180-5051","position":10,"is_corresponding":false},{"id":499266,"name":"Dane M. Chetkovich","orcid":"0000-0001-5993-2118","position":11,"is_corresponding":false},{"id":499263,"name":"Ye Han","orcid":"0000-0003-4687-7193","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:29:11.698554Z","pmid":"35623388","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}