Lipidation-dimerization platform unlocks treatment potential of fibroblast growth factor 21 for non-alcoholic steatohepatitis

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release Pub Date : 2024-11-09 DOI:10.1016/j.jconrel.2024.11.006

Yapeng Wang , Lei Shen , Chengcheng Wang , Yuanzhen Dong , Haoju Hua , Jun Xu , Ying Zhang , Hao Huang , Zongqing Huang , Fei Zhao , Zhiru Xu , Yunliang Qiu , Jianguang Lu , Dianwen Ju , Jun Feng

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Abstract

Optimizing the druggability of both native and AI-designed bioactive proteins is crucial for realizing their therapeutic potential. A key focus in designing protein-based therapeutics is improving their pharmacokinetic properties. However, a significant challenge is to preserve biological activity while implementing long-acting strategies. Fibroblast growth factor 21 (FGF21), an endogenous hormone with potential as a treatment for non-alcoholic steatohepatitis (NASH), exemplifies this challenge. In this study, we present a novel lipidation-dimerization (LiDi) platform that integrates lipidation with a dimeric form of FGF21 connected by a hydrophilic linker. The lipidation enhances albumin binding, enabling sustained release, while the dimeric structure boosts biological activity. In vivo evaluations of the LiDi FGF21 analogs demonstrated that they offer excellent pharmacokinetic properties and superior efficacy compared to other treatments for NASH. This platform effectively extends the therapeutic half-life of proteins without compromising their activity, substantially broadening the application range of proteins as therapeutics.

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脂肪二聚化平台释放成纤维细胞生长因子 21 治疗非酒精性脂肪性肝炎的潜力

优化原生蛋白质和人工智能设计的生物活性蛋白质的可药用性对于实现其治疗潜力至关重要。设计基于蛋白质的疗法的一个重点是改善其药代动力学特性。然而，如何在实施长效策略的同时保持生物活性是一个重大挑战。成纤维细胞生长因子 21（FGF21）是一种内源性激素，具有治疗非酒精性脂肪性肝炎（NASH）的潜力。在这项研究中，我们提出了一种新型脂化-二聚化（LiDi）平台，它将脂化与由亲水连接体连接的 FGF21 二聚体形式结合在一起。脂化增强了与白蛋白的结合，从而实现了持续释放，而二聚体结构则提高了生物活性。对 LiDi FGF21 类似物的体内评估表明，与其他治疗 NASH 的方法相比，它们具有出色的药代动力学特性和更优越的疗效。该平台有效延长了蛋白质的治疗半衰期，同时不影响其活性，大大拓宽了蛋白质作为治疗药物的应用范围。

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来源期刊

Journal of Controlled Release 医学-化学综合

CiteScore

18.50

自引率

5.60%

发文量

700

审稿时长

39 days

期刊介绍： The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.