{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:25:22Z","timestamp":1790439922833,"version":"4.1.0"},"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insufficient insulin secretion or impaired cellular response to insulin, resulting in increased blood sugar levels and persistent hyperglycemia. The diabetes-related health expenditure worldwide is estimated to have surpassed 1,000 billion USD according to the new data from the International Diabetes Federation. Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated high efficacy in glycemic control and body weight loss, is approved for T2DM and obesity treatment. However, up to now, industrial production of semaglutide remains constrained by limited yield and high cost associated with conventional approaches. Therefore, improving production efficiency while reducing manufacturing cost remains a challenge. In this study, we report a new strategy for obtaining semaglutide main chain P29, also known as Arg\n                    <jats:sup>34<\/jats:sup>\n                    GLP-1 (9\u201337), which is a key intermediate precursor in semaglutide synthesis. The method employs a series of semaglutide-derived helical fusion pro-peptides containing the sequence GSHHWHHHSSGDDDDK, which could be cleaved by a 2-step processing via sequence-specific nickel-assisted chemical protein cleavage followed by enterokinase cleavage. Using this strategy, semaglutide main chain P29 was highly expressed and purified to 98% purity, with yields exceeding 5 grams per liter of broth. This process provides improved productivity compared with previously reported strategies. The work establishes an efficient and scalable platform for semaglutide intermediate production and shows potential for large-scale industrial production.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0348509","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:25:48Z","timestamp":1782494748000},"page":"e0348509","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["High-yield recombinant production of the semaglutide main chain P29 intermediate using SNAC-tagged enterokinase-cleavable fusion peptides"],"prefix":"10.1371","volume":"21","author":[{"given":"Qingyu","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0911-6911","authenticated-orcid":true,"given":"Xianling","family":"Bian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"pone.0348509.ref001","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"H Sun","year":"2022","journal-title":"Diabetes Res Clin Pract"},{"key":"pone.0348509.ref002","doi-asserted-by":"crossref","first-page":"109083","DOI":"10.1016\/j.diabres.2021.109083","article-title":"Global estimates of incidence of type 1 diabetes in children and adolescents: Results from the International Diabetes Federation Atlas, 10th edition","volume":"183","author":"GD Ogle","year":"2022","journal-title":"Diabetes Res Clin Pract"},{"issue":"10397","key":"pone.0348509.ref003","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","article-title":"Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021","volume":"402","author":"GBD 2021 Diabetes Collaborators","year":"2023","journal-title":"Lancet"},{"key":"pone.0348509.ref004","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1016\/S0140-6736(24)02317-1","article-title":"Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants","volume":"404","author":"NCD Risk Factor Collaboration (NCD-RisC)","year":"2024","journal-title":"Lancet"},{"key":"pone.0348509.ref005","doi-asserted-by":"crossref","first-page":"112277","DOI":"10.1016\/j.diabres.2025.112277","article-title":"Global type 1 diabetes prevalence, incidence, and mortality estimates 2025: Results from the International diabetes Federation Atlas, 11th Edition, and the T1D Index Version 3.0","volume":"225","author":"GD Ogle","year":"2025","journal-title":"Diabetes Res Clin Pract"},{"key":"pone.0348509.ref006","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/164_2021_574","article-title":"Novel Drugs for Diabetes Therapy","volume":"274","author":"T Heise","year":"2022","journal-title":"Handb Exp Pharmacol"},{"key":"pone.0348509.ref007","doi-asserted-by":"crossref","first-page":"106550","DOI":"10.1016\/j.phrs.2022.106550","article-title":"Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment","volume":"186","author":"KO Kopp","year":"2022","journal-title":"Pharmacol Res"},{"issue":"8","key":"pone.0348509.ref008","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/s41581-024-00836-y","article-title":"Applications of SGLT2 inhibitors beyond glycaemic control","volume":"20","author":"DV O\u2019Hara","year":"2024","journal-title":"Nat Rev Nephrol"},{"issue":"3","key":"pone.0348509.ref009","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/dom.12825","article-title":"Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials","volume":"19","author":"D Li","year":"2017","journal-title":"Diabetes Obes Metab"},{"key":"pone.0348509.ref010","article-title":"9. 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