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

• DOI: 10.1126/sciadv.adt3943
• Publication Date: 2025-05-02T17:58:36Z
• Authors: 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

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.