The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral–human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B*40:01, HLA-B*40:02, and HLA-B*35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A*03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human–viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.

分子拟态在塑造 SARS-CoV-2 进化和免疫逃避方面的作用仍有待破译。在这里，我们报告了 33 种不同的 8 聚体/9 聚体肽，它们在 SARS-CoV-2 和人类参考蛋白质组之间是相同的。我们将这一观察结果与其他病毒-人类 8 聚体/9 聚体肽特性进行了比较，这表明 SARS-CoV-2 和许多其他人类病毒的分子模拟程度大致相似。有趣的是，在之前的任何冠状病毒毒株（HCoV、SARS-CoV 和 MERS）中都没有观察到 SARS-CoV-2 模仿的 20 种新型人类肽。此外，SARS-CoV-2 模拟的四种人类 8 聚体/9 聚体肽映射到来自 HLA-B*40:01、HLA-B*40:02 和 HLA-B*35:01 的结合肽上。人类 PAM、ANXA7、PGD 和 ALOX5AP 蛋白。单细胞 RNA 序列 (scRNA-seq) 分析使 SARS-CoV-2 对多种人类蛋白质的模仿变得突出，该分析显示目标基因在人类肺和动脉中显着表达；与 COVID-19 发病机制有关的组织。最后，发现人类和冠状病毒科解旋酶在功能热点中广泛共享 HLA-A*03 限制性 8 聚体肽，这对初始感染时的核酸解旋具有潜在影响。这项研究首次对 SARS-CoV-2 的人类肽拟态进行扫描，并通过更广泛地对人类病毒拟态进行基准测试，为后续研究提供了一个计算框架，以分析进化修补与人畜共患病和群体免疫之间的关系。