Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Core Facility Functional Peptidomics, Ulm University Medical Center, Ulm, Germany.
Nat Commun. 2021 Mar 19;12(1):1726. doi: 10.1038/s41467-021-21972-0.
SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α-antitrypsin (αAT), a highly abundant circulating serine protease inhibitor. Here, we report that αAT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that αAT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein αAT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of αAT-containing drugs has prospects for the therapy of COVID-19.
SARS-CoV-2 是一种呼吸道病原体，主要感染气道上皮细胞。由于我们对呼吸道固有免疫因子抵抗 SARS-CoV-2 的了解有限，因此我们生成并筛选了源自支气管肺泡灌洗液的肽/蛋白文库，以寻找抑制 SARS-CoV-2 刺突驱动进入的抑制剂。抗病毒部分的分析显示存在α-抗胰蛋白酶（αAT），这是一种丰富的循环丝氨酸蛋白酶抑制剂。在这里，我们报告αAT 以生理浓度抑制 SARS-CoV-2 的进入，并抑制包括人气道上皮培养物在内的细胞系和原代细胞中的病毒复制。我们进一步证明αAT 结合并失活丝氨酸蛋白酶 TMPRSS2，该酶可使 SARS-CoV-2 刺突蛋白进行膜融合。因此，急性期蛋白αAT 是 TMPRSS2 和 SARS-CoV-2 进入的抑制剂，可能在针对新型冠状病毒的先天免疫防御中发挥重要作用。我们的发现表明，含有αAT 的药物的再利用具有治疗 COVID-19 的前景。
