{"doi":"10.1016/j.apsb.2025.08.005","title":"Deciphering the significant impact of natural glycosylation on human insulin","abstract":"In the century-long evolution of insulin pharmaceuticals, each transformative advancement in this drug class has been closely tied to the ability to obtain new insulin isoforms for research. Despite this, the recently discovered naturally occurring isoforms of glycosylated human insulin have remained largely unattainable for proper characterization. Herein, we demonstrate for the first time that total chemical synthesis can be used to generate all isoforms. This achievement required maintaining the correct positions of the interchain disulfide bonds while effectively removing protecting groups on complex glycans. Notably, the availability of seven glycoforms reveals the important effects of natural sialylated glycans in suppressing insulin self-association and enhancing its solubility, surpassing the performance of currently employed rapid-acting insulin drugs. This work not only offers a readily adaptable platform for exploring natural O -glycosylation in other therapeutic proteins and peptides but also lays the groundwork for further research into harnessing natural glycosylation for therapeutic applications. This study reveals that natural O -glycosylation endows human insulin with significantly reduced self-association and enhanced solubility, outperforming currently marketed rapid-acting analogs in these properties.","journal":"Acta Pharmaceutica Sinica B","year":2025,"id":526545,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"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":1127841,"name":"Wenqiang Liu","orcid":"0009-0001-0618-4715","position":1,"is_corresponding":false},{"id":311110,"name":"Dan Liu","orcid":"0000-0002-2198-3910","position":2,"is_corresponding":false},{"id":590156,"name":"Ruihan Wang","orcid":"0000-0002-4169-4673","position":3,"is_corresponding":false},{"id":820907,"name":"Yajing Zhang","orcid":"0009-0000-2862-7102","position":4,"is_corresponding":false},{"id":1402072,"name":"Xin Li","orcid":"0000-0002-6411-2453","position":5,"is_corresponding":false},{"id":1127839,"name":"Jinyuan Gong","orcid":"0009-0009-4262-849X","position":6,"is_corresponding":false},{"id":297443,"name":"Shiying Shang","orcid":"0009-0005-5742-110X","position":7,"is_corresponding":false},{"id":297444,"name":"Zhongping Tan","orcid":"0000-0002-9302-150X","position":8,"is_corresponding":false},{"id":297442,"name":"Yaohao Li","orcid":"0000-0002-4333-9042","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:50:30.402772Z","pmid":"41311403","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":[]}