{"doi":"10.1101/2025.01.13.632834","title":"Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretion <i>in vitro</i> and <i>in vivo</i> of a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001","abstract":"Abstract The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought. Here, we describe the synthesis and properties of a molecule which binds to both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R and GIPR) to enhance insulin secretion. HISHS-2001 shows increased affinity at the GLP-1R, as well as a tendency towards reduced internalization and recycling at this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. HISHS-2001 also displayed significantly greater bias towards cAMP generation versus β-arrestin 2 recruitment compared to tirzepatide. In contrast, G αs recruitment was lower versus tirzepatide at the GLP-1R, but higher at the GIPR. Administered to obese hyperglycaemic db/db mice, HISHS-2001 increased circulating insulin whilst lowering body weight and HbA1c with similar efficacy to tirzepatide at substantially lower doses. Thus, HISHS-2001 represents a novel dual receptor agonist with an improved pharmacological profile.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555892,"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":0.9549,"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":260262,"name":"Ben Jones","orcid":"0000-0003-0461-2584","position":1,"is_corresponding":false},{"id":483198,"name":"Gaëlle Carrat","orcid":"0000-0003-1189-3441","position":2,"is_corresponding":false},{"id":1450799,"name":"Zenouska Ramchunder","orcid":"0009-0008-0194-2311","position":3,"is_corresponding":false},{"id":262816,"name":"Piero Marchetti","orcid":"0000-0003-4907-0635","position":4,"is_corresponding":false},{"id":350919,"name":"Isabelle Leclerc","orcid":"0000-0003-0044-7921","position":5,"is_corresponding":false},{"id":1451243,"name":"Rajamannar Thennati","orcid":null,"position":6,"is_corresponding":false},{"id":1450800,"name":"Vinod Burade","orcid":"0009-0008-3710-3667","position":7,"is_corresponding":false},{"id":1451244,"name":"Muthukumaran Natarajan","orcid":null,"position":8,"is_corresponding":false},{"id":1451245,"name":"Pradeep Shahi","orcid":null,"position":9,"is_corresponding":false},{"id":260266,"name":"Alejandra Tomás","orcid":"0000-0002-2290-8453","position":10,"is_corresponding":false},{"id":350920,"name":"Guy A. Rutter","orcid":"0000-0001-6360-0343","position":11,"is_corresponding":false},{"id":1450798,"name":"Yusman Manchanda","orcid":"0000-0002-2874-5608","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-19T02:55:03.976486Z","pmid":"39868265","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":[]}