{"doi":"10.1021/acsinfecdis.5c00329","title":"Chemical and Genetic Validation of an Essential Calcium Entry Channel of <i>Trypanosoma brucei</i> as a Therapeutic Target","abstract":"High Resolution Image Download MS PowerPoint Slide The Trypanosoma brucei group of parasites causes Nagana in cattle and human African trypanosomiasis, or sleeping sickness, in humans. Current drugs against these parasites have severe toxicity, vaccines are not available, and development of drug resistance makes finding new chemotherapeutic targets imperative. Ion channels, which are involved in several biological processes, are targets of many therapeutically useful agents, and they remain significantly underexplored as therapeutic targets in parasites. Here, we report the presence of a voltage gated Ca 2+ channel (VGCC, TbCa v ), which is localized in the flagellar plasma membrane (PM) of T. brucei and is essential for proliferation of both bloodstream (BSF) and procyclic forms (PCF) of the parasite. TbCa V is a single subunit channel capable of transporting Ca 2+ when expressed in mutant yeast lacking PM Ca 2+ channels or in HEK293T cells. Through the virtual screening of a commercial chemical library using dynamic ensembles of various conformations of TbCa v and associated docking analyses, several inhibitors of TbCa v were discovered. As pharmacological validation of the essential roles of TbCa v, these compounds were shown to inhibit T. brucei growth with the most potent agent, N -(7-nitro-2,1,3-benzoxadiazol-4-yl) acetamide (NBD-A), exhibiting an EC 50 of 25 ± 3 nM and no cytotoxicity in Vero cells possessing related channels. Thus, such studies constitute pharmacological validation of TbCa v as a viable therapeutic target of T. brucei .","journal":"ACS Infectious Diseases","year":2025,"id":541408,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1429752,"name":"Harmanpreet Singh","orcid":"0000-0002-2093-2468","position":1,"is_corresponding":false},{"id":1429753,"name":"Priti Chatterjee","orcid":"0000-0002-3287-9190","position":2,"is_corresponding":false},{"id":1429754,"name":"Rohit Kumar Varshnaya","orcid":"0000-0003-1506-7163","position":3,"is_corresponding":false},{"id":674227,"name":"Donald Hamelberg","orcid":"0000-0002-3785-3037","position":4,"is_corresponding":false},{"id":292038,"name":"Binghe Wang","orcid":"0000-0002-2200-5270","position":5,"is_corresponding":false},{"id":218760,"name":"Roberto Docampo","orcid":"0000-0003-4229-8784","position":6,"is_corresponding":false},{"id":437486,"name":"Guozhong Huang","orcid":"0000-0002-9150-6802","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:52:47.161928Z","pmid":"40462260","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":[]}