Rationally Designed ACE2-Derived Peptides Inhibit SARS-CoV-2,Bioconjugate Chemistry

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Rationally Designed ACE2-Derived Peptides Inhibit SARS-CoV-2
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-12-24 , DOI: 10.1021/acs.bioconjchem.0c00664
Ross C Larue ₁ , Enming Xing ₂ , Adam D Kenney ₃ , Yuexiu Zhang ₄ , Jasmine A Tuazon ₅ , Jianrong Li ₄ , Jacob S Yount ₃ , Pui-Kai Li ₂ , Amit Sharma _{3,

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Affiliation

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a novel and highly pathogenic coronavirus and is the causative agent of the coronavirus disease 2019 (COVID-19). The high morbidity and mortality associated with COVID-19 and the lack of an approved drug or vaccine for SARS-CoV-2 underscores the urgent need for developing effective antiviral therapies. Therapeutics that target essential viral proteins are effective at controlling virus replication and spread. Coronavirus Spike glycoproteins mediate viral entry and fusion with the host cell, and thus are essential for viral replication. To enter host cells, the Spike proteins of SARS-CoV-2 and related coronavirus, SARS-CoV, bind the host angiotensin-converting enzyme 2 (ACE2) receptor through their receptor binding domains (RBDs). Here, we rationally designed a panel of ACE2-derived peptides based on the RBD-ACE2 binding interfaces of SARS-CoV-2 and SARS-CoV. Using SARS-CoV-2 and SARS-CoV Spike-pseudotyped viruses, we found that a subset of peptides inhibits Spike-mediated infection with IC₅₀ values in the low millimolar range. We identified two peptides that bound Spike RBD in affinity precipitation assays and inhibited infection with genuine SARS-CoV-2. Moreover, these peptides inhibited the replication of a common cold causing coronavirus, which also uses ACE2 as its entry receptor. Results from the infection experiments and modeling of the peptides with Spike RBD identified a 6-amino-acid (Glu37-Gln42) ACE2 motif that is important for SARS-CoV-2 inhibition. Our work demonstrates the feasibility of inhibiting SARS-CoV-2 with peptide-based inhibitors. These findings will allow for the successful development of engineered peptides and peptidomimetic-based compounds for the treatment of COVID-19.

中文翻译：

合理设计的 ACE2 衍生肽可抑制 SARS-CoV-2

严重急性呼吸综合征冠状病毒 (SARS-CoV)-2 是一种新型高致病性冠状病毒，是 2019 年冠状病毒病 (COVID-19) 的病原体。与 COVID-19 相关的高发病率和死亡率以及缺乏针对 SARS-CoV-2 的批准药物或疫苗，凸显了开发有效抗病毒疗法的迫切需要。针对必需病毒蛋白的治疗可有效控制病毒复制和传播。冠状病毒刺突糖蛋白介导病毒进入宿主细胞并与宿主细胞融合，因此对于病毒复制至关重要。为了进入宿主细胞，SARS-CoV-2 和相关冠状病毒 SARS-CoV 的刺突蛋白通过其受体结合域 (RBD) 与宿主血管紧张素转换酶 2 (ACE2) 受体结合。在这里，我们基于 SARS-CoV-2 和 SARS-CoV 的 RBD-ACE2 结合界面，合理设计了一组 ACE2 衍生肽。使用 SARS-CoV-2 和 SARS-CoV Spike 假型病毒，我们发现一部分肽可抑制 Spike 介导的感染，IC ₅₀值在低毫摩尔范围内。我们在亲和沉淀测定中鉴定出两种结合 Spike RBD 的肽，并抑制真正的 SARS-CoV-2 的感染。此外，这些肽还能抑制引起普通感冒的冠状病毒的复制，这种冠状病毒也使用 ACE2 作为其进入受体。感染实验和使用 Spike RBD 进行肽建模的结果确定了一个 6 个氨基酸 (Glu37-Gln42) ACE2 基序，该基序对于抑制 SARS-CoV-2 非常重要。我们的工作证明了用基于肽的抑制剂抑制 SARS-CoV-2 的可行性。这些发现将有助于成功开发用于治疗 COVID-19 的工程肽和基于肽模拟物的化合物。

更新日期：2021-01-20

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