Back to Search Start Over

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

Authors :
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
Source :
Acta Pharmaceutica Sinica B, Vol 14, Iss 7, Pp 3232-3250 (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

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 dodecanamine-chitosan 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 AUC0‒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 UDP-glycosyltransferase (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.

Details

Language :
English
ISSN :
22113835
Volume :
14
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Acta Pharmaceutica Sinica B
Publication Type :
Academic Journal
Accession number :
edsdoj.25b34968aac42819ebddcb13d0f09a5
Document Type :
article
Full Text :
https://doi.org/10.1016/j.apsb.2024.03.005