The COVID-19 pandemic continues to spread around the world, with several new variants emerging, particularly those of concern (VOCs). Omicron (B.1.1.529), a recent VOC with many mutations in the spike protein’s receptor-binding domain (RBD), has attracted a great deal of scientific and public interest. We previously developed two D-peptide inhibitors for the infection of the original SARS-CoV-2 and its VOCs, alpha and beta, in vitro. Here, we demonstrated that Covid3 and Covid_extended_1 maintained their high-affinity binding (29.4–31.3 nM) to the omicron RBD. Both D-peptides blocked the omicron variant in vitro infection with IC50s of 3.13 and 5.56 μM, respectively. We predicted that Covid3 shares a larger overlapping binding region with the ACE2 binding motif than different classes of neutralizing monoclonal antibodies. We envisioned the design of D-peptide inhibitors targeting the receptor-binding motif as the most promising approach for inhibiting current and future VOCs of SARS-CoV-2, given that the ACE2 binding interface is more limited to tolerate mutations than most of the RBD’s surface.

中文翻译：

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用模仿 ACE2 结合螺旋的 D 肽靶向 SARS-CoV-2 的受体结合基序：抑制 Omicron 和未来值得关注的变体的经验教训

COVID-19 大流行继续在世界各地蔓延，并出现了几种新的变体，尤其是令人关注的变体 (VOC)。Omicron (B.1.1.529) 是一种最新的 VOC，在刺突蛋白的受体结合域 (RBD) 中存在许多突变，引起了科学界和公众的极大兴趣。我们之前开发了两种 D 肽抑制剂，用于体外感染原始 SARS-CoV-2 及其 VOC（α 和 β）。在这里，我们证明了 Covid3 和 Covid_extended_1 保持了与 omicron RBD 的高亲和力结合 (29.4–31.3 nM)。两种 D 肽均可阻断 omicron 变体的体外感染，IC50 分别为 3.13 和 5.56 μM。我们预测，与不同类别的中和单克隆抗体相比，Covid3 与 ACE2 结合基序共享更大的重叠结合区域。鉴于 ACE2 结合界面比大多数 RBD 的耐受突变更有限，我们设想针对受体结合基序的 D 肽抑制剂的设计是抑制 SARS-CoV-2 当前和未来 VOC 的最有前途的方法表面。