Development of a Decafluorobiphenyl Cyclized Peptide Targeting the NEMO-IKKα/β Interaction that Enhances Cell Penetration and Attenuates Lipopolysaccharide-Induced Acute Lung Injury

  • Bioconjug Chem. 2024 May 15;35(5):638-652. doi: 10.1021/acs.bioconjchem.4c00122.
Shu Li  1  2 ,  Shibo Song  1 ,  Xiaojing Liu  1 ,  Xingjiao Zhang  1 ,  Xueya Liang  1 ,  Xin Chang  1 ,  Daijun Zhou  1 ,  Jianting Han  1 ,  Yaoyan Nie  1 ,  Chen Guo  1 ,  Xiaojun Yao  3 ,  Min Chang  1 ,  Yali Peng  1
Affiliations
  • 1. Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
  • 2. Key Laboratory of Xinjiang Endemic Phytomedicine Resources Ministry of Education, Shihezi University College of Pharmacy, Shihezi 832003, Xinjiang, China.
  • 3. State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
PMID: 38669628 DOI: 10.1021/acs.bioconjchem.4c00122
Abstract

Aberrant canonical NF-κB signaling has been implicated in diseases, such as autoimmune disorders and Cancer. Direct disruption of the interaction of NEMO and IKKα/β has been developed as a novel way to inhibit the overactivation of NF-κB. Peptides are a potential solution for disrupting protein-protein interactions (PPIs); however, they typically suffer from poor stability in vivo and limited tissue penetration permeability, hampering their widespread use as new chemical biology tools and potential therapeutics. In this work, decafluorobiphenyl-cysteine SNAr chemistry, molecular modeling, and biological validation allowed the development of peptide PPI inhibitors. The resulting cyclic peptide specifically inhibited canonical NF-κB signaling in vitro and in vivo, and presented positive metabolic stability, anti-inflammatory effects, and low cytotoxicity. Importantly, our results also revealed that cyclic peptides had huge potential in acute lung injury (ALI) treatment, and confirmed the role of the decafluorobiphenyl-based cyclization strategy in enhancing the biological activity of peptide NEMO-IKKα/β inhibitors. Moreover, it provided a promising method for the development of peptide-PPI inhibitors.

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