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Ferritin Nanocage-Based Methyltransferase SETD6 for COVID-19 Therapy

机译：基于铁蛋白的纳米病基甲基转移酶SetD6用于Covid-19疗法

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摘要

The transcription factor nuclear factor-kappa B (NF-kappa B) signaling is a mediator of viral infection-mediated inflammation and SET-domain containing 6 (SETD6) is known as a methyltransferase that suppresses the activity of NF-kappa B signaling. However, the downside of the SETD6 is that it cannot be directly utilized as an inflammatory regulator due to the short half-life and poor intracellular delivery. Here, a ferritin nanocage-based delivery system is presented that can maintain the activity of SETD6 in vivo. According to the analysis of severe COVID-19 patients' peripheral blood mononuclear cells (PBMCs), the SETD6 expression is downregulated while that of NF-kappa B is upregulated. By engineering the structure of ferritin, a protein scaffold is fabricated in which short ferritin is decorated with cell-penetrating peptide and nuclear-localizing TAT-NBD peptide together with SETD6, termed TFS. The TFS enhances the SETD6 level and reduces the NF-kappa B signaling in PBMCs of severe COVID-19 patients and subsequently suppresses the cytokine storm. When the TFS is intravenously administered in the cytokine storm mouse model, the survival rate is rescued and the lung tissue damage and cytokine expression are also inhibited. These results indicate that the ferritin nanocage-based peptide delivery system allows stable in vivo delivery and efficient suppression of NF-kappa B signaling-mediated inflammation.
机译：转录因子核因子-Kappa（NF-Kappa）信号传导是病毒感染介导的炎症的介质，并且含有6（SetD6）的设定结构域被称为甲基转移酶，其抑制NF-κB信号传导的活性。然而，SetD6的缺点是由于短的半衰期和细胞内递送差，它不能直接用作炎症调节因子。这里，提出了一种铁蛋白纳米载体的递送系统，其可以维持体内SetD6的活性。根据严重CoVID-19患者外周血单核细胞（PBMC）的分析，在上调NF-Kappa B的SETD6表达时，使得NF-Kappa B的表达下降。通过工程铁蛋白的结构，制造一种蛋白质支架，其中短铁蛋白用细胞穿透肽和核定位的TAT-NBD肽与SETD6一起装饰，称为TF。 TFS增强了SETD6水平，并减少了严重Covid-19患者的PBMC中的NF-Kappa B信号，随后抑制了细胞因子风暴。当在细胞因子雨小鼠模型中静脉内施用TFS时，救出存活率，并且还抑制了肺组织损伤和细胞因子表达。这些结果表明，铁蛋白纳米型肽输送系统允许稳定的体内递送和有效抑制NF-Kappa B发信号介导的炎症。

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  • 来源
    《Advanced Functional Materials》 |2020年第48期|2006110.1-2006110.10|共10页
  • 作者

    Kim Hong Nam; Park Hee Ho; Lim Wonhee; Hong Kyung Soo; Ahn June Hong; Na Dong Hee; Kim In-San; Jang Jong Geol; Bae Jong-Sup; Lee Wonhwa;

  • 作者单位

    Korea Inst Sci & Technol KIST Brain Sci Inst Ctr BioMicrosyst Seoul 02792 South Korea|Korea Univ Sci & Technol KIST Sch Div Biomed Sci & Technol Seoul 02792 South Korea;

    Kangwon Natl Univ Dept Biotechnol & Bioengn Chunchon 24341 Gangwon Do South Korea;

    Korea Res Inst Biosci & Biotechnol Rare Dis Res Ctr Daejeon 34141 South Korea|Univ Sci & Technol Dept Funct Genom Daejeon 34141 South Korea;

    Yeungnam Univ Coll Med Dept Internal Med Div Pulmonol & Allergy Daegu 42415 South Korea|Yeungnam Univ Med Ctr Reg Ctr Resp Dis Daegu 42415 South Korea;

    Yeungnam Univ Coll Med Dept Internal Med Div Pulmonol & Allergy Daegu 42415 South Korea|Yeungnam Univ Med Ctr Reg Ctr Resp Dis Daegu 42415 South Korea;

    Chung Ang Univ Coll Pharm Seoul 06974 South Korea;

    Korea Inst Sci & Technol Biomed Res Inst Seoul 02792 South Korea|Korea Univ KU KIST Grad Sch Converging Sci & Technol Seoul 02841 South Korea;

    Yeungnam Univ Coll Med Dept Internal Med Div Pulmonol & Allergy Daegu 42415 South Korea|Yeungnam Univ Med Ctr Reg Ctr Resp Dis Daegu 42415 South Korea;

    Kyungpook Natl Univ Plus KNU Multiom Based Creat Drug Res Team BK21 Res Inst Pharmaceut Sci Coll Pharm CMRI Daegu 41566 South Korea;

    Korea Res Inst Biosci & Biotechnol Aging Res Ctr Daejeon 34141 South Korea;

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  • 正文语种 eng
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  • 关键词

    COVID-19; cytokine storm; ferritin; NF-kappa B signaling; SETD6;

    机译：Covid-19;细胞因子风暴;铁蛋白;NF-Kappa发信息;SetD6;

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