{"doi":"10.1101/2020.09.01.278291","title":"A novel phospholipid mimetic targeting LRH-1 ameliorates colitis","abstract":"Abstract Phospholipids are ligands for nuclear hormone receptors (NRs) and regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions greatly improves agonists of liver receptor homolog-1 (LRH-1), a promising therapeutic target for diabetes and colitis. Conventional LRH-1 modulators partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of hybrid molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. The phospholipid-mimicking group improves binding affinity, increases LRH-1 transcriptional activity, promotes coregulator recruitment, and interacts with the targeted LRH-1 residues in crystal structures. The best new agonist markedly improves colonic histopathology and disease-related weight loss in a humanized LRH-1 murine T-cell transfer model of colitis. This is the first evidence of in vivo efficacy for an LRH-1 modulator in colitis, a leap forward in agonist development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127309,"datarank":0.12264848599134967,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.018676408907357864,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.018676408907357864,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":383302,"name":"Emma H. D’Agostino","orcid":"0000-0002-0902-4274","position":1,"is_corresponding":false},{"id":575998,"name":"Autumn R. Flynn","orcid":"0000-0003-2504-2365","position":2,"is_corresponding":false},{"id":107266,"name":"Xiangsheng Huang","orcid":"0000-0003-0363-2006","position":3,"is_corresponding":false},{"id":575999,"name":"Guohui Wang","orcid":"0000-0002-0749-6059","position":4,"is_corresponding":false},{"id":366621,"name":"Xu Liu","orcid":"0000-0003-2252-7148","position":5,"is_corresponding":false},{"id":576000,"name":"Elizabeth J. Millings","orcid":"0000-0002-2077-9985","position":6,"is_corresponding":false},{"id":362425,"name":"C. Denise Okafor","orcid":"0000-0001-7374-1561","position":7,"is_corresponding":false},{"id":362023,"name":"Anamika Patel","orcid":"0000-0003-4760-9019","position":8,"is_corresponding":false},{"id":398189,"name":"Michael L. Cato","orcid":"0000-0002-5008-202X","position":9,"is_corresponding":false},{"id":398995,"name":"Jeffery L. Cornelison","orcid":null,"position":10,"is_corresponding":false},{"id":576616,"name":"Dianna Melchers","orcid":null,"position":11,"is_corresponding":false},{"id":384687,"name":"René Houtman","orcid":"0000-0001-7639-6310","position":12,"is_corresponding":false},{"id":323913,"name":"David D. Moore","orcid":"0000-0002-5151-9748","position":13,"is_corresponding":false},{"id":407559,"name":"John W. Calvert","orcid":"0000-0001-6858-6042","position":14,"is_corresponding":false},{"id":398190,"name":"Nathan T. Jui","orcid":"0000-0001-5315-0270","position":15,"is_corresponding":false},{"id":74596,"name":"Eric A. Ortlund","orcid":"0000-0001-8855-3029","position":16,"is_corresponding":false},{"id":383301,"name":"Suzanne G. Mays","orcid":"0000-0003-0220-0885","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:15:30.930746Z","pmid":null,"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":[]}