Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury

Zhang, Le; Xu, Lijuan; Chen, Haihu; Zhang, Wannian; Xing, Chengguo; Qu, Zhuo; Yu, Jian‐Qiang; Zhuang, Chunlin

doi:10.1016/j.ejmech.2021.113599

Cited by 25 publications

(21 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 Our group developed several potent Keap1−Nrf2 inhibitors applying the aminonaphthalene scaffold for the treatment of lipopolysaccharide (LPS)-induced cardiomyopathy, myocarditis, Alzheimer's disease, and acute lung injury. 10,35,42,43 The inhibitor NXPZ-2 showed great potency (Figure 1, K D2 = 230 nM, determined by a fluorescence anisotropy assay) and was predicted to bind with the highly positively charged binding pocket of Keap1, and the diamide group was proposed to face the solvent exposed region for structural optimization. 35 However, this compound has a limited solubility due to its high hydrophobicity and symmetry properties.…”

Section: Introductionmentioning

confidence: 99%

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

Liu

Hou

et al. 2022

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Directly inhibiting the Keap1–Nrf2 protein–protein interaction has been investigated as a promising strategy to activate Nrf2 for anti-inflammation. We previously reported a naphthalensulfonamide Keap1–Nrf2 inhibitor NXPZ-2, but have not determined the exact binding mode with Keap1. This symmetric naphthalenesulfonamide compound has relatively low solubility. Herein, we first determined a crystal complex (resolution: 2.3 Å) of human Keap1 Kelch domain with NXPZ-2. Further optimizations on the solvent exposed region obtained asymmetric naphthalenesulfonamides and three crystal structures of Keap1 in complex with designed compounds. Among them, the asymmetric piperazinyl-naphthalenesulfonamide 6k with better aqueous solubility showed the best K D2 value of 0.21 μM to block the interaction. The productions of ROS and NO and the expression of TNF-α were inhibited by 6k in the in vitro model. This compound could relieve inflammations by significantly increasing the Nrf2 nuclear translocation in the LPS-induced ALI model with promising pharmacokinetic properties.

show abstract

Section: Introductionmentioning

confidence: 99%

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

Liu

Hou

et al. 2022

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Specifically, Huang et al [ 27 ] suggest that this pathway regulates endoplasmic reticulum stress, apoptosis, and autophagy to attenuate the LPS-induced ALI. Hu et al [ 28 ] demonstrate that the Nrf2-Keap1-antioxidant response element (ARE) signaling pathway can eliminate oxidative stress and its associated inflammation to improve traumatic lung injury-related pathology, and a Keap1-Nrf2 inhibitor designed by Zhang et al is expected to be a novel protective agent of ALI [ 29 ]. In addition, it has been reported that some drugs and compounds can alleviate lung injury by regulating Keap1-Nrf2 pathways, such as ginsenoside Rh2 [ 30 ], sinomenine [ 31 ], and panaxydol [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Sevoflurane reduces lipopolysaccharide-induced apoptosis and pulmonary fibrosis in the RAW264.7 cells and mice models to ameliorate acute lung injury by eliminating oxidative damages

Zheng

Zhang

et al. 2022

Redox Report

View full text Add to dashboard Cite

Objectives Sevoflurane is identified as an effective candidate drug for acute lung injury (ALI) treatment, but its curing effects and detailed mechanisms have not been fully disclosed. The present study was designed to resolve this academic issue. Methods The ALI mice models were established, and Hematoxylin-eosin staining assay was performed to examine tissue morphologies. Cell viability was determined by CCK-8 assay, and Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The expression levels of proteins were determined by performing Western Blot analysis and immunofluorescence staining assay. ROS levels were examined by using DCFH-DA staining assay. Results In this study, we investigated this issue and the ALI models were respectively established by treating the BALB/c mice and the murine macrophage cell line RAW264.7 with different concentrations of lipopolysaccharide (LPS) in vivo and in vitro, which were subsequently subjected to sevoflurane co-treatment. The results showed that sevoflurane reduced LPS-induced ALI in mice and suppressed LPS-triggered oxidative stress and apoptotic cell death in the RAW264.7 cells. Interestingly, we evidenced that the elimination of reactive oxygen species (ROS) by N-acetyl-L-cysteine (NAC) reversed LPS-induced cell apoptosis in RAW264.7 cells. Then, we verified that sevoflurane suppressed oxidative damages to restrain LPS-induced apoptotic cell death in the RAW264.7 cells through activating the anti-oxidant Keap1/Nrf2 pathway. Mechanistically, sevoflurane down-regulated Keap1 and upregulated Nrf2 in nucleus to activate the downstream anti-oxidant signaling cascades, which further ameliorated LPS-induced cell apoptosis and lung injury by eliminating oxidative damages. Discussion Taken together, our study illustrated that the sevoflurane attenuates LPS-induced ALI by inhibiting oxidative stress-mediated apoptotic cell death and inflammation, and the Keap1/Nrf2 pathway played an important role in this process.

show abstract

“…Naphthalene-sulfonamide derivative SCN-16 has been reported to inhibit interaction with Keap1 and Nrf2, which reduced lung damage. SCN-16 increased nuclear Nrf2, HO-1, and NQO-1 and significantly reduced inflammation in the LPS-induced ALI model [44]. Moreover, treatment of sulforaphane after hyperoxia exposure not only inhibited lung injury but also improved energy metabolism in mitochondria and cardiovascular function in mice [45].…”

Section: Ards/alimentioning

confidence: 95%

An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches

Lee

Jang

Park

et al. 2021

IJMS

View full text Add to dashboard Cite

Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 by binding to Nrf2 and contributes to Nrf2 break down by ubiquitin proteasomes. In moderate oxidative stress, Keap1 is inhibited, allowing Nrf2 to be translocated to the nucleus, which acts as an antioxidant. However, under unusually severe oxidative stress, the Keap1-Nrf2 mechanism becomes disrupted and results in cell and tissue damage. Oxide-containing atmospheric environment generally contributes to the development of respiratory diseases, possibly leading to the failure of the Keap1-Nrf2 pathway. Until now, several studies have identified changes in Keap1-Nrf2 signaling in models of respiratory diseases, such as acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma. These studies have confirmed that several Nrf2 activators can alleviate symptoms of respiratory diseases. Thus, this review describes how the expression of Keap1-Nrf2 functions in different respiratory diseases and explains the protective effects of reversing this expression.

show abstract

Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury

Cited by 25 publications

References 39 publications

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

Sevoflurane reduces lipopolysaccharide-induced apoptosis and pulmonary fibrosis in the RAW264.7 cells and mice models to ameliorate acute lung injury by eliminating oxidative damages

An Update on the Role of Nrf2 in Respiratory Disease: Molecular Mechanisms and Therapeutic Approaches

Contact Info

Product

Resources

About