The hexameric α-helical coiled-coil formed between the C-terminal and N-terminal heptad repeat (CHR and NHR) regions of class I viral fusion proteins plays an important role in mediating the fusion of the viral and cellular membranes and provides a clear starting point for molecular mimicry that drives viral fusion inhibitor design. Unfortunately, such peptide mimicry of the short α-helical region in the CHR of Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein has been thwarted by the loss of the peptide’s native α-helical conformation when taken out of the parent protein structure. Here, we describe that appropriate all-hydrocarbon stapling of the short helical portion-based peptide to reinforce its bioactive secondary structure remarkably improves antiviral potency. The resultant stapled peptide P21S10 could effectively inhibit infection by MERS-CoV pseudovirus and its spike protein-mediated cell–cell fusion; additionally, P21S10 exhibits improved pharmacokinetic properties than HR2P-M2, suggesting strong potential for development as an anti-MERS-CoV therapeutic.

中文翻译：

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发现碳氢化合物短α-螺旋肽作为有希望的中东呼吸系统综合症冠状病毒（MERS-CoV）融合抑制剂

在I类病毒融合蛋白的C端和N端七肽重复序列（CHR和NHR）之间形成的六聚体α-螺旋卷曲螺旋在介导病毒膜和细胞膜的融合中起着重要作用，并提供了清晰的驱动病毒融合抑制剂设计的分子模拟的起点。不幸的是，中东呼吸综合征冠状病毒（MERS-CoV）刺突蛋白CHR的CHR中短α螺旋区的这种肽模拟物被当从母体蛋白结构中取出时，其肽的天然α螺旋构象的丢失而受到阻碍。 。在这里，我们描述了适当的全碳氢化合物短螺旋部分基于肽的装订，以增强其生物活性二级结构显着提高了抗病毒效力。由此产生的固定肽P21S10可以有效抑制MERS-CoV假病毒及其刺突蛋白介导的细胞间融合感染。此外，与HR2P-M2相比，P21S10表现出更高的药代动力学特性，表明其作为抗MERS-CoV治疗剂具有强大的开发潜力。