{"title":"Rational Design of Site-Specific Fatty Acid Derivatives to Extend the Half-Life of Fibroblast Growth Factor 21.","authors":"Chengcheng Wang, Yapeng Wang, Yuanzhen Dong, Yu Duan, Ying Zhang, Hao Huang, Zhiru Xu, Jianguang Lu, Chunyong Ding, Zhengyan Cai, Dianwen Ju, Jun Feng","doi":"10.1021/acs.bioconjchem.4c00549","DOIUrl":null,"url":null,"abstract":"<p><p>Fibroblast growth factor 21 (FGF21) is a crucial regulator of glucose and lipid metabolism, showing significant therapeutic promise for metabolic disorders. However, its clinical application is limited by poor pharmacokinetics. One potential strategy to improve its half-life is to facilitate albumin binding through fatty acid derivation. Despite this promise, achieving site-specific modifications of FGF21 while preserving its biological activity has been challenging. In this study, we applied a rational design approach to create site-specific fatty acid derivatives of FGF21, guided by the structure of the FGF21-receptor complex. This strategy successfully enhances albumin binding without interfering with receptor interactions. The modified FGF21 derivatives exhibited dramatically extended half-lives in mice, increasing from 0.73 h to 11.36 and 13.36 h, respectively. Furthermore, these analogues showed superior biological activity in the presence of albumin, outperforming the C-terminal-derived variant zalfermin. This rational design approach not only improves the pharmacokinetic profile of FGF21 but also provides a framework for enhancing the therapeutic potential of other small proteins.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":" ","pages":""},"PeriodicalIF":4.0000,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioconjugate Chemistry","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1021/acs.bioconjchem.4c00549","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 0
Abstract
Fibroblast growth factor 21 (FGF21) is a crucial regulator of glucose and lipid metabolism, showing significant therapeutic promise for metabolic disorders. However, its clinical application is limited by poor pharmacokinetics. One potential strategy to improve its half-life is to facilitate albumin binding through fatty acid derivation. Despite this promise, achieving site-specific modifications of FGF21 while preserving its biological activity has been challenging. In this study, we applied a rational design approach to create site-specific fatty acid derivatives of FGF21, guided by the structure of the FGF21-receptor complex. This strategy successfully enhances albumin binding without interfering with receptor interactions. The modified FGF21 derivatives exhibited dramatically extended half-lives in mice, increasing from 0.73 h to 11.36 and 13.36 h, respectively. Furthermore, these analogues showed superior biological activity in the presence of albumin, outperforming the C-terminal-derived variant zalfermin. This rational design approach not only improves the pharmacokinetic profile of FGF21 but also provides a framework for enhancing the therapeutic potential of other small proteins.
期刊介绍:
Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecular conjugates.