Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor

Jiang, Zhengyu; Xu, Lili; Lu, Meng-Chen; Chen, Zhiyun; Yuan, Zhenwei; Xu, Xiu; Guo, Xiaoke; Zhang, Xiaojin; Sun, Haopeng; You, Qidong

doi:10.1021/acs.jmedchem.5b00185

Cited by 75 publications

(78 citation statements)

References 28 publications

(57 reference statements)

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“…antioxidant and detoxifying enzymes (61). Therefore, Nrf2 has potential as a therapeutic target for liver diseases, including APAP-induced hepatotoxicity (62).…”

Section: Discussionmentioning

confidence: 99%

PYP1‑4 peptide from Pyropia yezoensis protects against acetaminophen‑induced hepatotoxicity in HepG2 cells

2019

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Acetaminophen (APAP) is a widely used analgesic and antipyretic. It is safe at normal treatment doses; however, APAP overdose is a major cause of acute liver and kidney failure. A variety of methods to reduce the damage caused by APAP overdose have previously been evaluated. The protein-rich seaweed Pyropia yezoensis has antioxidant, antitumor and anti-inflammatory activities, and protects against cytotoxicity. However, little is known regarding the protective effects of P. yezoensis peptide against APAP-induced hepatotoxicity. The present study investigated the ability of P. yezoensis peptide (PYP1-4) to ameliorate the damage caused by APAP-induced hepatotoxicity using HepG2 as the model cell line in addition to the signaling pathways involved. Briefly, cell viability, nitric oxide, reactive oxygen species and apoptosis assays were performed in conjunction with western blot analysis and reverse transcription-quantitative PCR. First, the present study revealed the minimum toxic concentration of APAP (15 mM) and the resting concentration of PYP1-4 (0-500 ng/ml). Administration of PYP1-4 to APAP-induced cells decreased the nitric oxide and reactive oxygen species levels, and restored the levels of antioxidant-associated proteins (catalase, heme oxygenase 1, superoxide dismutase 2 and quinone oxidoreductase 1). PYP1-4 increased the translocation of nuclear factor, erythroid 2 like 2 to the nucleus and the activities of glycogen synthase kinase-3β, Akt and AMP-activated protein kinase. In addition, APAP induced apoptosis; however, PYP1-4 inhibited apoptosis by modulating the levels of pro-apoptotic markers (Bad), anti-apoptotic markers (Bcl-2 and BH3 interacting domain death agonist), caspases and poly (ADP-ribose) polymerase 1. Subsequently, the insulin-like growth factor 1 receptor signaling pathway was investigated to determine whether PYP1-4 treatment restored the levels of cell growth-associated factors during APAP-induced hepatotoxicity. PYP1-4 treatment impacted the levels of components of the insulin receptor substrate 1/PI3K/Akt and Ras/Raf/ERK signaling pathways, and promoted cell survival. Therefore, the P. yezoensis peptide PYP1-4 may be useful for preventing APAP-induced hepatotoxicity.

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“…antioxidant and detoxifying enzymes (61). Therefore, Nrf2 has potential as a therapeutic target for liver diseases, including APAP-induced hepatotoxicity (62).…”

Section: Discussionmentioning

confidence: 99%

PYP1‑4 peptide from Pyropia yezoensis protects against acetaminophen‑induced hepatotoxicity in HepG2 cells

2019

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“…A recent study on structural activity and structure-property relationships of a proposed inhibitor recognised the presence of a symmetric structure with an aromatic ring in the centre that could tether to the hydrophobic binding segment inside the central core of the protein. The symmetric modification of benzene rings at the ends of the structure could increase the potency of the drug (Jiang et al 2015).…”

Section: Chemical Inhibitors Of Keap1mentioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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“…24,25 The diacetate moiety can form multiple polar interactions, including hydrogen bonds and salt bridges, with key polar residues, especially arginines in the P1 and P2 subpockets. However, the diacetic acid moiety is highly polar and easily ionized, which may possess potential hurdles in druggability issues.…”

Section: ■ Design and Synthesis Of Compounds With Various Bioisosterimentioning

confidence: 99%

“…The different side chains were introduced by the electrophilic substitution of the sulfonamides, which have been used to construct the diacetic compound series (Scheme 1). 24,25 ■ DITETRAZOLE ANALOG CAN MAINTAIN THE…”

Section: ■ Design and Synthesis Of Compounds With Various Bioisosterimentioning

confidence: 99%

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

Tan

et al. 2016

ACS Med. Chem. Lett.

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Directly disrupting the Keap1-Nrf2 protein−protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC 50 = 15.8 nM) in an in vitro fluorescence polarization assay. Physicochemical property determination demonstrated that ditetrazole replacement can improve the drug-like property, including elevation of pK a , log D, and transcellular permeability. Additionally, 7 is more efficacious than 2 on inducing the expression of Nrf2-dependent gene products in cells. This study provides an alternative way to replace the diacetic moiety and occupy the polar subpockets in Keap1, which can benefit the subsequent development of Keap1-Nrf2 PPI inhibitor.

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Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor

Cited by 75 publications

References 28 publications

PYP1‑4 peptide from Pyropia yezoensis protects against acetaminophen‑induced hepatotoxicity in HepG2 cells

PYP1‑4 peptide from Pyropia yezoensis protects against acetaminophen‑induced hepatotoxicity in HepG2 cells

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Polar Recognition Group Study of Keap1-Nrf2 Protein–Protein Interaction Inhibitors

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