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首页> 外文期刊>Biochemistry >Rationally Designed Peptides as Efficient Inhibitors of Nucleic Acid Chaperone Activity of HIV-1 Nucleocapsid Protein
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Rationally Designed Peptides as Efficient Inhibitors of Nucleic Acid Chaperone Activity of HIV-1 Nucleocapsid Protein

机译：理性设计的肽作为HIV-1核衣壳蛋白核酸伴核酸伴蛋白活性的有效抑制剂

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摘要

Due to its essential roles in the viral replication cycle and to its highly conserved sequence, the nucleocapsid protein (NCp7) of the human immunodeficiency virus type 1 is a target of choice for inhibiting replication of the virus. Most NCp7 inhibitors identified so far are small molecules. A small number of short peptides also act as NCp7 inhibitors by competing with its nucleic acid (NA) binding and chaperone activities but exhibit antiviral activity only at relatively high concentrations. In this work, in order to obtain more potent NCp7 competitors, we designed a library of longer peptides (10-17 amino acids) whose sequences include most of the NCp7 structural determinants responsible for its specific NA binding and destabilizing activities. Using an in vitro assay, the most active peptide (pE) was found to inhibit the NCp7 destabilizing activity, with a 50% inhibitory concentration in the nanomolar range, by competing with NCp7 for binding to its NA substrates. Formulated with a cell-penetrating peptide (CPP), pE was found to accumulate into HeLa cells, with low cytotoxicity. However, either formulated with a CPP or overexpressed in cells, pE did not show any antiviral activity. In vitro competition experiments revealed that its poor antiviral activity may be partly due to its sequestration by cellular RNAs. The selected peptide pE therefore appears to be a useful tool for investigating NCp7 properties and functions in vitro, but further work will be needed to design pE-derived peptides with antiviral activity.
机译：由于病毒复制周期和其高度保守序列的基本作用，人免疫缺陷病毒类型1的核衣壳蛋白（NCP7）是抑制病毒复制的选择的目标。到目前为止鉴定的大多数NCP7抑制剂是小分子。通过与其核酸（Na）结合和伴侣活性竞争，少量短肽也充当NCP7抑制剂，而是仅在相对高浓度下表现出抗病毒活性。在这项工作中，为了获得更多有效的NCP7竞争对手，我们设计了一种较长的肽（10-17个氨基酸）的文库，其序列包括其特定Na结合和稳定活性的大多数NCP7结构决定簇。使用体外测定，发现最活性的肽（PE）抑制NCP7稳定活性，通过竞争NCP7与其Na底物结合，纳米摩尔范围内的50％抑制浓度。用细胞穿透肽（CPP）配制，发现PE积聚到Hela细胞中，具有低细胞毒性。但是，在细胞中用CPP或过表达配制，PE没有显示任何抗病毒活性。体外竞争实验表明，其抗病毒活性差可能部分是由于其通过细胞RNA的封存。因此，所选择的肽PE似乎是用于研究NCP7性能和体外功能的有用工具，但是将需要进一步的作用来设计具有抗病毒活性的体育肽。

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  • 来源
    《Biochemistry》 |2018年第30期|共12页
  • 作者

    Shvadchak Volodymyr; Zgheib Sarwat; Basta Beata; Humbert Nicolas; Langedijk Johannes; Morris May C.; Ciaco Stefano; Maskri Ouerdia; Darlix Jean-Luc; Mauffret Olivier; Fosse Philippe; Real Eleonore; Mely Yves;

  • 作者单位

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

    Pepscan Therapeut BV Lelystad Netherlands;

    Univ Montpellier Fac Pharm Inst Biomol Max Mousseron CNRS UMR 5247 15 Av Charles Flahault F-34093 Montpellier France;

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

    Univ Paris Saclay CNRS ENS Paris Saclay LBPA F-94235 Cachan France;

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

    Univ Paris Saclay CNRS ENS Paris Saclay LBPA F-94235 Cachan France;

    Univ Paris Saclay CNRS ENS Paris Saclay LBPA F-94235 Cachan France;

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

    Univ Strasbourg Lab Bioimaging &

    Pathol CNRS UMR 7021 74 Route Rhin F-67401 Illkirch Graffenstaden France;

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  • 正文语种 eng
  • 中图分类 生物化学;
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