A rationally designed injury kidney targeting peptide library and its application in rescuing acute kidney injury

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-05-02 DOI:10.1126/sciadv.adt3943

Yushuo Xiao, Zhijian Tong, Huidie Xu, Zhouyan Jia, Chen Wang, Yang Cao, Liangliang Song, Siyu Hao, Jing Yang, Yihao Zhou, Yunhao Xie, Peng Wu, Tong He, Yancai Wu, Robert B. Petersen, Anlin Peng, Chun Zhang, Hong Chen, Ling Zheng, Kun Huang

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Abstract

Acute kidney injury (AKI) has high incidence and mortality rates. Present treatments are mostly symptomatic and cause side effects due to systemic distribution; thus, targeted kidney drug delivery is desired. Transmembrane kidney injury molecule-1 (KIM1) is expressed at low levels in normal kidneys but markedly up-regulated following injury, making it an ideal marker/target for injured kidneys. Here, assisted by AlphaFold, we constructed a library of 1885 peptides that target the extracellular Ig V domain of KIM1 based on interacting fragments from 47 potential KIM1 binding proteins followed by systemic optimization according to their binding energies with KIM1. Experimental validation of top candidates (TKP 1-5) demonstrated that TKP 4 efficiently targeted injured renal cells/kidneys, with its specificity demonstrated in KIM1 knockout cells/mice. TKP 4–decorating liposomes were loaded with nystatin, a renal-protective compound with systemic side effects, and efficiently targeted injured mouse kidneys and alleviated AKI. This work establishes a virtual platform to screen/identify drug delivery candidates with broad research/therapeutic potentials.

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合理设计损伤肾靶向肽文库及其在急性肾损伤抢救中的应用

急性肾损伤（AKI）具有很高的发病率和死亡率。目前的治疗大多是对症治疗，由于全身分布而引起副作用；因此，需要有针对性的肾脏给药。跨膜肾损伤分子-1 （KIM1）在正常肾脏中表达水平较低，但在损伤后显著上调，使其成为损伤肾脏的理想标记物/靶标。在AlphaFold的帮助下，我们基于47个潜在的KIM1结合蛋白的相互作用片段构建了一个1885个靶向KIM1细胞外Ig V结构域的肽库，并根据它们与KIM1的结合能进行了系统优化。对候选药物（TKP 1-5）的实验验证表明，TKP 4有效地靶向损伤的肾细胞/肾脏，其特异性在KIM1敲除细胞/小鼠中得到证实。TKP - 4修饰脂质体装载制霉素（一种具有全身副作用的肾脏保护化合物），有效靶向损伤小鼠肾脏并减轻AKI。这项工作建立了一个虚拟平台来筛选/识别具有广泛研究/治疗潜力的药物输送候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.