Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany.
Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany.
EBioMedicine. 2021 Mar;65:103255. doi: 10.1016/j.ebiom.2021.103255. Epub 2021 Mar 4.
Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated.
We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA.
We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity.
Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA.
NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.
需要抗病毒药物来对抗由 SARS-CoV-2 引起的 COVID-19 大流行。已临床证明的蛋白酶抑制剂卡莫司他甲磺酸盐通过阻断病毒激活宿主细胞蛋白酶 TMPRSS2 来抑制 SARS-CoV-2 感染。然而，卡莫司他甲磺酸盐代谢物的抗病毒活性和潜在的病毒耐药性尚未得到分析。此外，卡莫司他甲磺酸盐在人肺组织中的抗病毒活性仍有待证明。
我们使用重组 TMPRSS2、带有 SARS-CoV-2 刺突蛋白的报告颗粒或真实的 SARS-CoV-2 来分别评估卡莫司他甲磺酸盐及其代谢物 GBPA 对 TMPRSS2 的抑制作用和病毒进入。
我们表明几种与 TMPRSS2 相关的蛋白酶可激活 SARS-CoV-2，其中两种，TMPRSS11D 和 TMPRSS13，在上呼吸道中大量表达。然而，Camostat 甲磺酸盐可阻断这些蛋白酶介导的进入。与 Camostat 甲磺酸盐相比，Camostat 的代谢物 GBPA 抑制重组 TMPRSS2 的效率降低。相比之下，两种抑制剂均表现出相似的抗病毒活性，这与在存在血清时 Camostat 甲磺酸盐快速转化为 GBPA 相关。最后，Camostat 甲磺酸盐和 GBPA 阻断了 SARS-CoV-2 在人肺组织中的传播，相关蛋白酶抑制剂 Nafamostat 甲磺酸盐表现出增强的抗病毒活性。
我们的结果表明，SARS-CoV-2 可以使用 TMPRSS2 和密切相关的蛋白酶在上呼吸道中传播，Camostat 甲磺酸盐和其代谢物 GBPA 可以阻断在人肺中的传播。
NIH、Damon Runyon 基金会、ACS、NYCT、DFG、欧盟、柏林数学中心 MATH+、BMBF、下萨克森州、Lundbeck 基金会、诺和诺德基金会。
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