A bioactive ligand-conjugated iridium(III) metal-based complex as a Keap1–Nrf2 protein-protein interaction inhibitor against acetaminophen-induced acute liver injury
Guodong Li,
Hao Liu,
Ruibing Feng,
Tian-Shu Kang,
Wanhe Wang,
Chung-Nga Ko,
Chun-Yuen Wong,
Min Ye,
Dik-Lung Ma,
Jian-Bo Wan,
Chung-Hang Leung
Affiliations
Guodong Li
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
Hao Liu
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
Ruibing Feng
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
Tian-Shu Kang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
Wanhe Wang
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China; Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
Chung-Nga Ko
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
Chun-Yuen Wong
Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Hong Kong SAR, China
Min Ye
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
Dik-Lung Ma
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China; Corresponding author.
Jian-Bo Wan
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China; Corresponding author.
Chung-Hang Leung
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China; Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, China; Corresponding author. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao.
Hepatotoxicity caused by an overdose of acetaminophen (APAP) is the leading reason for acute drug-related liver failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein that helps to regulate redox homeostasis and coordinate stress responses via binding to the Kelch-like ECH-associated protein 1 (Keap1). Targeting the Keap1-Nrf2 interaction has recently emerged as a potential strategy to alleviate liver injury caused by APAP. Here, we designed and synthesized a number of iridium (III) and rhodium (III) complexes bearing ligands with reported activity against oxidative stress, which is associated with Nrf2 transcriptional activation. The iridium (III) complex 1 bearing a bioactive ligand 2,9-dimethyl-1,10-phenanthroline and 4-chloro-2-phenylquinoline, a derivative of the bioactive ligand 2-phenylquinoline, was identified as a direct small-molecule inhibitor of the Keap1–Nrf2 protein-protein interaction. 1 could stabilize Keap1 protein, upregulate HO-1 and NQO1, and promote Nrf2 nuclear translocation in normal liver cells. Moreover, 1 reversed APAP-induced liver damage by disrupting Keap1–Nrf2 interaction and without inducing organ damage and immunotoxicity in mice. Our study demonstrates the identification of a selective and efficacious antagonist of Keap1–Nrf2 interaction possessed good cellular permeability in cellulo and ideal pharmacokinetic parameters in vivo, and, more importantly, validates the feasibility of conjugating metal complexes with bioactive ligands to generate metal-based drug leads as non-toxic Keap1–Nrf2 interaction inhibitors for treating APAP-induced acute liver injury.
