2. Academic Validation
  3. Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury

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

  • Eur J Med Chem. 2021 Oct 15:222:113599. doi: 10.1016/j.ejmech.2021.113599.
Le Zhang 1,  Lijuan Xu 1,  Haihu Chen 2,  Wannian Zhang 1,  Chengguo Xing 3,  Zhuo Qu 4,  Jianqiang Yu 5,  Chunlin Zhuang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 2 Department of Intervention, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
  • 3 Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
  • 4 School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: quzhuo2008@163.com.
  • 5 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: yujq910315@163.com.
  • 6 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: zclnathan@163.com.
PMID: 34119834 DOI: 10.1016/j.ejmech.2021.113599
Abstract

Blocking the Kelch-like epichlorohydrin-related protein 1 (Keap1)-nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway represents as a promising strategy to reduce oxidative stress and related-inflammation, including acute lung injury (ALI). NXPZ-2, a naphthalensulfonamide derivative, was previously reported to effectively inhibit the Keap1-Nrf2 protein-protein interaction (PPI) by our group. In the present work, a series of novel isothiocyanate-containing naphthalensulfonamides with the thioether, sulfoxide and sulfone moieties were designed by a structure-based molecular hybridization strategy using NXPZ-2 and the Nrf2 activator sulforaphane. They possessed good Keap1-Nrf2 PPI inhibitory activity and low cytotoxicity. The molecular docking study was performed to further explain the different activity of the thioether-, sulfoxide- and sulfone-containing naphthalensulfonamides. Among these new derivatives, 2-((N-(4-((N-(2-amino-2-oxoethyl)-4-((3-isothiocyanatopropyl)sulfinyl)phenyl)sulfonamido) naphthalen-1-yl)-4-methoxyphenyl)sulfonamido)acetamide (SCN-16) showed a good KD2 value of 0.455 μM to disrupt the PPI. In an LPS-induced peritoneal macrophage cell model, this compound could cause a significant increase in the nuclear Nrf2 protein, decrease in the cytosolic Nrf2 protein, and further elevate the downstream protective Enzymes HO-1 and NQO-1, which were better than the lead compound NXPZ-2 and sulforaphane. What's more, the production of ROS and NO and the expression of pro-inflammatory cytokine TNF-α were also suppressed. In the LPS-induced ALI model, SCN-16 could significantly reduce LPS-induced inflammations and alleviate lung injuries by triggering Nrf2 nuclear translocation. Collectively, our results suggested that SCN-16 could be a novel lead compound targeting Keap1-Nrf2 protective pathway for clinical treatment of ALI.

Keywords

Acute lung injury; Anti-inflammation; Keap1-Nrf2; Molecular hybridization; Naphthalensulfonamides; Protein-protein interaction.

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