Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2-Priming Protease TMPRSS2.
Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2-Priming Protease TMPRSS2.
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DOI：
10.20411/pai.v6i1.408
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发表时间：
2021
影响因子：
--
通讯作者：
Rothenberg ME
中科院分区：
文献类型：
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作者：
Azouz NP;Klingler AM;Callahan V;Akhrymuk IV;Elez K;Raich L;Henry BM;Benoit JL;Benoit SW;Noé F;Kehn-Hall K;Rothenberg ME
宿主蛋白酶被认为是MERS、SARS-CoV和SARS-CoV-2冠状病毒传播的关键，但膜蛋白酶与细胞内蛋白酶的相对贡献仍有争议。跨膜丝氨酸蛋白酶2（Transmembrane serine protease 2，TMPRSS 2）被认为是冠状病毒S蛋白引发的主要蛋白酶之一，S蛋白在进入细胞前与血管紧张素转换酶2（angiotensin-converting enzyme 2，ACE 2）受体结合的重要步骤。我们开发了一种基于细胞的测定来鉴定TMPRSS 2抑制剂。在SARS-CoV-2病毒载量系统中建立了抑制活性。我们鉴定了人细胞外丝氨酸蛋白酶抑制剂（serpin）α 1抗胰蛋白酶（A1 AT）作为新型TMPRSS 2抑制剂。结构建模显示，A1 AT对接到TMPRSS 2的细胞外结构域的构象，适合催化，类似于类似的丝氨酸蛋白酶抑制剂复合物。在SARS-CoV-2病毒载量系统中建立了A1 AT的抑制活性。值得注意的是，血浆A1 AT水平与COVID-19疾病严重程度相关。我们的数据支持细胞外丝氨酸蛋白酶在SARS CoV-2感染中的关键作用，并表明用丝氨酸蛋白酶抑制剂治疗，特别是FDA批准的药物A1 AT，可能通过影响宿主细胞的表面来有效限制SARS-CoV-2传播。
Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry. We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems. We identified the human extracellular serine protease inhibitor (serpin) alpha 1 anti-trypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity. Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.