A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization  

作　　者：Ping Yu Tanwei Gu Yueyang Rao Weimin Liang Xi Zhang Huanguo Jiang Jindi Lu Jianglian She Jianmin Guo Wei Yang Yonghong Liu Yingfeng Tu Lan Tang Xuefeng Zhou 

机构地区：[1]Guangdong Provincial Key Laboratory of New Drug Screening,Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology,Guangdong Key Laboratory of Marine Materia Medica,South China Sea Institute of Oceanology,Chinese Academy of Sciences,Guangzhou 510301,China [3]NMPA Key Laboratory for Research and Evaluation of Drug Metabolism,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [4]Guangdong Lewwin Pharmaceutical Research Institute Co.,Ltd.,Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research,Guangdong Engineering Research Center for Innovative Drug Evaluation and Research,Guangzhou 510990,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期3232-3250,共19页药学学报（英文版）

基　　金：supported by the Guangdong Local Innovation Team Program(2019BT02Y262,China);National Natural Science Foundation of China(U20A20101,82274002,22175083);Key-Area Research and Development Program of Guangdong Province(2023B1111050008,China);National Key Research and Development Program of China(2022YFA1206900,2023YFA0914200);Science and Technology Innovation Project of Guangdong Medical Products Administration(S2021ZDZ042,2023ZDZ06,2024ZDZ08,China).

摘　　要：Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

关 键 词：Acute kidney injury Piericidin glycoside Peroxiredoxin 1 Nanodrug Kim-1 targeted ADME Marine drug Druggability 

分 类 号：R69[医药卫生—泌尿科学] R96[医药卫生—外科学]