Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity.
Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity.
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DOI：
10.1016/j.ebiom.2021.103255
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发表时间：
2021-03
期刊：
影响因子：
11.1
通讯作者：
Pöhlmann S
中科院分区：
文献类型：
--
作者：
Hoffmann M;Hofmann-Winkler H;Smith JC;Krüger N;Arora P;Sørensen LK;Søgaard OS;Hasselstrøm JB;Winkler M;Hempel T;Raich L;Olsson S;Danov O;Jonigk D;Yamazoe T;Yamatsuta K;Mizuno H;Ludwig S;Noé F;Kjolby M;Braun A;Sheltzer JM;Pöhlmann S
对抗由SARS-CoV-2引起的COVID-19大流行需要抗病毒药物。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活化宿主细胞蛋白酶TMPRSS 2来抑制SARS-CoV-2感染。然而，尚未分析卡莫司他甲磺酸盐代谢产物的抗病毒活性和潜在的病毒耐药性。此外，甲磺酸卡莫司他在人肺组织中的抗病毒活性仍有待证实。我们使用重组TMPRSS 2，携带SARS-CoV-2或真实SARS-CoV-2刺突蛋白的报告颗粒，分别评估甲磺酸卡莫司他及其代谢物GBPA对TMPRSS 2和病毒进入的抑制。我们发现，几个TMPRSS 2相关的蛋白酶激活SARS-CoV-2和两个，TMPRSS 11 D和TMPRSS 13，在上呼吸道强烈表达。然而，由这些蛋白酶介导的进入被卡莫司他甲磺酸盐阻断。与甲磺酸卡莫司他相比，卡莫司他代谢物GBPA以降低的效率抑制重组TMPRSS 2。相反，两种抑制剂表现出相似的抗病毒活性，这与在血清存在下卡莫司他甲磺酸盐快速转化为GBPA相关。最后，卡莫司他甲磺酸盐和GBPA阻断了SARS-CoV-2在人肺组织中的离体传播，相关的蛋白酶抑制剂萘莫司他甲磺酸盐发挥了增强的抗病毒活性。我们的研究结果表明，SARS-CoV-2可以使用TMPRSS 2和密切相关的蛋白酶在上呼吸道传播，并且在人肺中的传播可以被卡莫司他甲磺酸盐及其代谢产物GBPA阻断。NIH、Damon Runyon基金会、ACS、NYCT、DFG、EU、柏林数学中心MATH+、BMBF、Lower萨克森、Lundbeck基金会、诺和诺德基金会。
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.
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影响因子：
--
作者：
Hofmann-Winkler H;Moerer O;Alt-Epping S;Bräuer A;Büttner B;Müller M;Fricke T;Grundmann J;Harnisch LO;Heise D;Kernchen A;Pressler M;Stephani C;Tampe B;Kaul A;Gärtner S;Kramer S;Pöhlmann S;Winkler MS
通讯作者：
Winkler MS
影响因子：
6.7
作者：
Hatesuer B;Bertram S;Mehnert N;Bahgat MM;Nelson PS;Pöhlmann S;Schughart K
通讯作者：
Schughart K
DOI：
10.1007/bf01852177
发表时间：
1987-01-01
期刊：
RESEARCH IN EXPERIMENTAL MEDICINE
影响因子：
--
作者：
BECKH, K;GOKE, B;ARNOLD, R
通讯作者：
ARNOLD, R
影响因子：
8.4
作者：
Hempel T;Raich L;Olsson S;Azouz NP;Klingler AM;Hoffmann M;Pöhlmann S;Rothenberg ME;Noé F
通讯作者：
Noé F
影响因子：
5.4
作者：
Laporte, Manon;Stevaert, Annelies;Naesens, Lieve
通讯作者：
Naesens, Lieve