Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein.
Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein.
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DOI：
10.1073/pnas.2210990119
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发表时间：
2022-10-04
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染需要病毒和宿主细胞膜的融合，由病毒刺突糖蛋白（S）介导。由于病毒膜融合的重要性，S已经成为开发疫苗和治疗剂的流行靶标。我们发现了一种简单的肽，可以抑制SARS-CoV-2所有主要变体的感染，其效力为纳摩尔。与此形成鲜明对比的是，广泛使用的缺乏关键N-末端延伸的较短肽的效力比该肽低约100倍。我们的研究结果表明，具有合适序列的简单肽可以成为对抗2019冠状病毒病的有效且具有成本效益的治疗方法，并且它们为病毒进入机制提供了新的见解。严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的变体通过病毒刺突糖蛋白受体结合结构域上的表位变化挑战了目前可用的冠状病毒疾病2019疫苗和单克隆抗体疗法。因此，特别迫切需要靶向不太可能受突变影响的过程的替代抗病毒药物，例如病毒进入宿主细胞的膜融合步骤。一类这样的抗病毒药物包括肽抑制剂，其阻断SARS-CoV-2刺突蛋白的所谓七肽重复1和2（HR 1HR 2）六螺旋束的形成，从而干扰病毒膜融合。我们进行了结构研究的HR 1HR 2束，揭示了一个扩展的，折叠良好的N-末端区域的HR 2与HR 1三螺旋相互作用。基于这种结构，我们设计了一种延伸的HR 2肽，在基于细胞和基于病毒的测定中实现了对SARS-CoV-2的单位数纳摩尔抑制，而不需要进行修饰，如脂化或化学钉合。该肽还强烈抑制迄今为止所有主要的SARS-CoV-2变体。这种延伸肽的效力是所有先前发表的短的、未修饰的HR 2肽的100倍，并且在病毒感染试验中洗脱后具有非常长的抑制寿命，这表明它靶向SARS-CoV-2 S蛋白的前发夹中间体。总之，这些结果表明，HR 2螺旋区以外的区域可能为SARS-CoV-2及其变体，甚至更远的相关病毒的有效肽衍生治疗提供新的机会，并为S蛋白的prehairpin中间体提供进一步的支持。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires fusion of viral and host membranes, mediated by the viral spike glycoprotein (S). Due to the importance of viral membrane fusion, S has been a popular target for developing vaccines and therapeutics. We discovered a simple peptide that inhibits infection by all major variants of SARS-CoV-2 with nanomolar efficacies. In marked contrast, widely used shorter peptides that lack a key N-terminal extension are about 100 times less potent than this peptide. Our results suggest that a simple peptide with a suitable sequence can be a potent and cost-effective therapeutic against coronavirus disease 2019, and they provide new insights into the virus entry mechanism. Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is ∼100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein.
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影响因子：
1
作者：
Monteiro A;Yu KOA;Hicar MD
通讯作者：
Hicar MD
影响因子：
5.4
作者：
Gao, Jing;Lu, Guangwen;Gao, George F.
通讯作者：
Gao, George F.
影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
影响因子：
56.9
作者：
Cai, Yongfei;Zhang, Jun;Chen, Bing
通讯作者：
Chen, Bing
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K