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Potent influenza A virus entry inhibitors targeting a conserved region of hemagglutinin

机译：有效的流感靶向血凝素保守区域的病毒进入抑制剂

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摘要

Graphical abstract A potent influenza A virus entry blocker of S-KKWK was created by conjugating the cholesterol with a peptide of KKWK. Its antiviral activity and modes investigated. Display Omitted Abstract Influenza A viruses (IAVs) induce acute respiratory disease and cause significant morbidity and mortality throughout the world. With the emergence of drug-resistant viral strains, new and effective anti-IAV drugs with different modes of action are urgently needed. In this study, by conjugating cholesterol to the N-terminus of the short peptide KKWK, a lipopeptide named S-KKWK was created. The anti-IAV test indicated that S-KKWK and its derivatives displayed potent antiviral activities against a broad variety of influenza A viral strains including oseltamivir-resistant strains and clinically relevant isolates with IC 50 values ranging from 0.7 to 3.0μM. An extensive mechanistic study showed that these peptides functioned as viral “entry blockers” by inhibiting the conformational rearrangements of HA2 subunit, thereby interrupting the fusion of virus-host cell membranes. Significantly, a computer-aided docking simulation and protein sequence alignment identified conserved residues in the stem region of HA2 as the possible binding site of S-KKWK, which may be employed as a potential drug target for designing anti-IAVs with a broad-spectrum of activity. By targeting this region, a potent anti-IAV agent was subsequently created. In addition, the anti-IAV activity of S-KKWK was assessed by experiments with influenza A virus-infected mice, in which S-KKWK reduced the mortality of infected animals and extended survival time significantly. Overall, in addition to providing a strategy for designing broad-spectrum anti-IAV agents, these results indicate that S-KKWK and its derivatives are prospective candidates for potent antivirals. ]]>
机译：图形摘要通过将胆固醇与Kkwk的肽缀合来创建一种有效的流感病毒入口障碍物。其抗病毒活动和模式调查。显示省略的抽象流感病毒（IAV）诱发急性呼吸道疾病，并在全世界引起显着的发病和死亡率。随着耐药性病毒菌株的出现，迫切需要具有不同作用方式的新抗IAV药物。在本研究中，通过将胆固醇缀合到短肽KKWK的N-末端，产生了名为S-KKWK的脂肽。抗IAV试验表明，S-KKWK及其衍生物针对广泛的流感抗病毒药物呈现有效的抗病毒活性，包括奥司霉菌抗性菌株和IC 50值的临床相关分离物，范围为0.7至3.0μm。广泛的机械研究表明，通过抑制HA2亚基的构象重排，这些肽作为病毒“入口阻断剂”，从而中断病毒 - 宿主细胞膜的融合。值得注意的是，作为S-KKWK的可能结合位点，将计算机辅助对接模拟和蛋白质序列对准鉴定在HA2的茎区域中的保守残留物，其可以用作设计具有广谱抗IAV的潜在药物靶标活动。通过靶向该区域，随后产生效率的抗IAV剂。此外，S-KKWK的抗IAV活性由流感的病毒感染小鼠进行评估，其中S-KKWK降低了感染动物的死亡率并显着延长存活时间。总体而言，除了为设计广谱抗IAV代理商提供策略之外，这些结果表明，S-KKWK及其衍生物是有效抗病毒药人的潜在候选人。 ]]>

著录项

  • 来源
    《Biochemical Pharmacology》 |2017年第2017期|共17页
  • 作者

    Dongguo Lin; Yinzhu Luo; Guang Yang; Fangfang Li; Xiangkun Xie; Daiwei Chen; Lifang He; Jingyu Wang; Chunfeng Ye; Shengsheng Lu; Lin Lv; Shuwen Liu; Jian He;

  • 作者单位

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Guangdong Laboratory Animals Monitoring Institute Guangdong Provincial Key Laboratory of;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Guangdong Laboratory Animals Monitoring Institute Guangdong Provincial Key Laboratory of;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

    Group of Peptides and Natural Products Research Guangdong Provincial Key Laboratory of New Drug;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    Anti-influenza A viruses; Cholesterol conjugated peptides; Virus entry inhibitors; Conserved region of hemagglutinin;

    机译：抗流感病毒;胆固醇共轭肽;病毒进入抑制剂;保守区域血凝素;

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