Shu Li, Shibo Song, Xiaojing Liu, Xingjiao Zhang, Xueya Liang, Xin Chang, Daijun Zhou, Jianting Han, Yaoyan Nie, Chen Guo, Xiaojun Yao, Min Chang* and Yali Peng*,
{"title":"开发针对 NEMO-IKKα/β 相互作用的十氟联苯环化肽,增强细胞穿透力并减轻脂多糖诱导的急性肺损伤","authors":"Shu Li, Shibo Song, Xiaojing Liu, Xingjiao Zhang, Xueya Liang, Xin Chang, Daijun Zhou, Jianting Han, Yaoyan Nie, Chen Guo, Xiaojun Yao, Min Chang* and Yali Peng*, ","doi":"10.1021/acs.bioconjchem.4c00122","DOIUrl":null,"url":null,"abstract":"<p >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 <i>in vivo</i> and limited tissue penetration permeability, hampering their widespread use as new chemical biology tools and potential therapeutics. In this work, decafluorobiphenyl-cysteine S<sub>N</sub>Ar chemistry, molecular modeling, and biological validation allowed the development of peptide PPI inhibitors. The resulting cyclic peptide specifically inhibited canonical NF-κB signaling <i>in vitro</i> and <i>in vivo</i>, 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.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of a Decafluorobiphenyl Cyclized Peptide Targeting the NEMO–IKKα/β Interaction that Enhances Cell Penetration and Attenuates Lipopolysaccharide-Induced Acute Lung Injury\",\"authors\":\"Shu Li, Shibo Song, Xiaojing Liu, Xingjiao Zhang, Xueya Liang, Xin Chang, Daijun Zhou, Jianting Han, Yaoyan Nie, Chen Guo, Xiaojun Yao, Min Chang* and Yali Peng*, \",\"doi\":\"10.1021/acs.bioconjchem.4c00122\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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 <i>in vivo</i> and limited tissue penetration permeability, hampering their widespread use as new chemical biology tools and potential therapeutics. In this work, decafluorobiphenyl-cysteine S<sub>N</sub>Ar chemistry, molecular modeling, and biological validation allowed the development of peptide PPI inhibitors. The resulting cyclic peptide specifically inhibited canonical NF-κB signaling <i>in vitro</i> and <i>in vivo</i>, 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.</p>\",\"PeriodicalId\":29,\"journal\":{\"name\":\"Bioconjugate Chemistry Bioconjugate\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-04-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioconjugate Chemistry Bioconjugate\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.bioconjchem.4c00122\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioconjugate Chemistry Bioconjugate","FirstCategoryId":"1","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.bioconjchem.4c00122","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
Development of a Decafluorobiphenyl Cyclized Peptide Targeting the NEMO–IKKα/β Interaction that Enhances Cell Penetration and Attenuates Lipopolysaccharide-Induced Acute Lung Injury
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.
期刊介绍:
Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecular conjugates.