Xiao Yushuo, Tong Zhijian, Xu Huidie, Jia Zhouyan, Wang Chen, Cao Yang, Song Liangliang, Hao Siyu, Yang Jing, Zhou Yihao, Xie Yunhao, Wu Peng, He Tong, Wu Yancai, Petersen Robert B, Peng Anlin, Zhang Chun, Chen Hong, Zheng Ling, Huang Kun
School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China.
State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430072, China.
Sci Adv. 2025 May 2;11(18):eadt3943. doi: 10.1126/sciadv.adt3943.
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.
急性肾损伤（AKI）的发病率和死亡率都很高。目前的治疗大多是对症治疗，且由于全身分布会产生副作用；因此，需要进行靶向肾脏给药。跨膜肾损伤分子-1（KIM1）在正常肾脏中低水平表达，但在损伤后会显著上调，使其成为受损肾脏的理想标志物/靶点。在这里，在AlphaFold的辅助下，我们基于47种潜在KIM1结合蛋白的相互作用片段构建了一个针对KIM1细胞外Ig V结构域的1885种肽的文库，然后根据它们与KIM1的结合能进行系统优化。对顶级候选物（TKP 1-5）的实验验证表明，TKP 4能有效靶向受损肾细胞/肾脏，其特异性在KIM1基因敲除细胞/小鼠中得到证实。用制霉菌素装载TKP 4修饰的脂质体，制霉菌素是一种有全身副作用的肾脏保护化合物，能有效靶向受损小鼠肾脏并减轻急性肾损伤。这项工作建立了一个虚拟平台，用于筛选/鉴定具有广泛研究/治疗潜力的药物递送候选物。
