Linear and dendrimeric antiviral peptides: design, chemical synthesis and activity against human respiratory syncytial virus.,Journal of Materials Chemistry B

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Linear and dendrimeric antiviral peptides: design, chemical synthesis and activity against human respiratory syncytial virus.
Journal of Materials Chemistry B ( IF 6.1 ) Pub Date : 2020/03/03 , DOI: 10.1039/c9tb02485a
Ksenia V Kozhikhova ₁ , Igor P Shilovskiy ₁ , Artem A Shatilov ₂ , Anastasiia V Timofeeva ₂ , Evgeny A Turetskiy ₂ , Liudmila I Vishniakova ₁ , Aleksandr A Nikolskii ₁ , Ekaterina D Barvinskaya ₁ , Subramani Karthikeyan ₃ , Valeriy V Smirnov ₂ , Dmitriy A Kudlay ₁ , Sergey M Andreev ₁ , Musa R Khaitov ₁

Affiliation

Respiratory syncytial virus (RSV) is one of the most common viral pathogens. It is especially dangerous for newborns and young children. In some cases it could lead to severe bronchiolitis, pneumonia with hospitalization or even a lethal outcome. Despite decades of investigation of RSV biology, effective and safe therapeutics are still under development. Certain natural peptides have been found to exhibit antiviral activity against respiratory viruses, but their implementation is limited by low stability in biological media. One of the current approaches to enhance the peptide therapeutic opportunities is chemical synthesis of peptide dendrimers with hyperbranched structures. Taking into account the recent data of bioactive cationic and helical regions of natural peptides and the structure features of nucleolin identified as an RSV cellular receptor, the main goal of this study was to design relatively short linear and dendrimeric cationic peptides and to test their antiviral activity against RSV. As a result 3 linear cationic peptides and 4 peptide dendrimers were synthesized and compared with known LL-37 (cathelicidin family) and anti-F0 monoclonal antibodies in terms of cytotoxicity and antiviral activity. Their affinity to the supposed molecular target - nucleolin (C23) - was estimated in silico by molecular docking analysis. Four synthesized peptides demonstrated a cytotoxic effect, two of them were even more cytotoxic than LL-37, which could be explained by a combination of a high amount of positive charge and amphipathicity. Contrariwise, non-hydrophobic dendrimer peptides did not exhibit cytotoxicity in mammalian cells in the studied concentration range. Two of the seven synthesized peptides, LTP (dendrimer) and SA-35 (linear), used in this study had a stronger antiviral effect than natural peptide LL-37, and three others showed slightly lower activity than anti-F0 monoclonal antibodies. The data obtained in this study suggest that evenly distributed positive charge, and low or medium amphipathicity play a key role in the antiviral activity of the studied peptides. Moreover, the calculated free energy values of the peptide/nucleolin complex for the most active peptides supported the idea that the peptide ability of nucleolin interaction promotes the anti-RSV properties of the molecules.

中文翻译：

线性和树状抗病毒肽：设计，化学合成和针对人类呼吸道合胞病毒的活性。

呼吸道合胞病毒（RSV）是最常见的病毒病原体之一。这对新生儿和幼儿特别危险。在某些情况下，它可能导致严重的毛细支气管炎，住院治疗的肺炎甚至致命的后果。尽管对RSV生物学进行了数十年的研究，但仍在开发有效且安全的疗法。已经发现某些天然肽对呼吸道病毒表现出抗病毒活性，但是其实施受到生物介质中低稳定性的限制。当前增加肽治疗机会的方法之一是化学合成具有超支化结构的肽树状聚合物。考虑到天然肽具有生物活性的阳离子和螺旋区的最新数据以及被鉴定为RSV细胞受体的核仁素的结构特征，本研究的主要目的是设计相对较短的线性和树状阳离子肽，并测试其抗病毒活性针对RSV。结果，合成了3种线性阳离子肽和4种肽树状聚合物，并且在细胞毒性和抗病毒活性方面与已知的LL-37（cathelicidin家族）和抗F0单克隆抗体进行了比较。通过分子对接分析在计算机上估算了它们与假定的分子靶标-核仁素（C23）的亲和力。四种合成的肽具有细胞毒性作用，其中两种比LL-37更具细胞毒性，这可以用大量的正电荷和两亲性结合来解释。相反，在所研究的浓度范围内，非疏水性树状大分子肽在哺乳动物细胞中未显示出细胞毒性。在这项研究中使用的七个合成肽中的两个LTP（树状大分子）和SA-35（线性）比天然肽LL-37具有更强的抗病毒作用，另外三个显示出比抗F0单克隆抗体稍低的活性。在这项研究中获得的数据表明，正电荷均匀分布，低或中等两亲性在所研究的肽的抗病毒活性中起关键作用。此外，

更新日期：2020-04-01

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