Cell Type-Specific Anti-Viral Effects of Novel SARS-CoV-2 Main Protease Inhibitors

Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals agains...

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Published in:	International journal of molecular sciences Vol. 24; no. 4; p. 3972
Main Authors:	Geiger, Nina, Diesendorf, Viktoria, Roll, Valeria, König, Eva-Maria, Obernolte, Helena, Sewald, Katherina, Breidenbach, Julian, Pillaiyar, Thanigaimalai, Gütschow, Michael, Müller, Christa E., Bodem, Jochen
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 16.02.2023 MDPI
Subjects:	Analysis Antiviral drugs Cell culture Cell growth Communication Coronaviruses Cytotoxicity Enzymes Genomes Health aspects Hepatitis C HIV Human immunodeficiency virus Immunization Infections Patients Protease inhibitors Proteases Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Viruses Germany cell line specificity pyridyl indole carboxylates protease inhibitors SARS-CoV-2 peptidomimetics azapeptide nitriles
ISSN:	1422-0067, 1661-6596, 1422-0067
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Abstract	Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals against SARS-CoV-2 act in a cell line-specific way. Thus, the compounds were tested in Vero, Huh-7, and Calu-3 cells. We showed that the protease inhibitors at 30 µM suppress viral replication by up to 5 orders of magnitude in Huh-7 cells, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates inhibited viral replication in all cell lines, indicating that they might repress viral replication in human tissue as well. Thus, we investigated three compounds in human precision-cut lung slices and observed donor-dependent antiviral activity in this patient-near system. Our results provide evidence that even direct-acting antivirals may act in a cell line-specific manner.
AbstractList	Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals against SARS-CoV-2 act in a cell line-specific way. Thus, the compounds were tested in Vero, Huh-7, and Calu-3 cells. We showed that the protease inhibitors at 30 µM suppress viral replication by up to 5 orders of magnitude in Huh-7 cells, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates inhibited viral replication in all cell lines, indicating that they might repress viral replication in human tissue as well. Thus, we investigated three compounds in human precision-cut lung slices and observed donor-dependent antiviral activity in this patient-near system. Our results provide evidence that even direct-acting antivirals may act in a cell line-specific manner.Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals against SARS-CoV-2 act in a cell line-specific way. Thus, the compounds were tested in Vero, Huh-7, and Calu-3 cells. We showed that the protease inhibitors at 30 µM suppress viral replication by up to 5 orders of magnitude in Huh-7 cells, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates inhibited viral replication in all cell lines, indicating that they might repress viral replication in human tissue as well. Thus, we investigated three compounds in human precision-cut lung slices and observed donor-dependent antiviral activity in this patient-near system. Our results provide evidence that even direct-acting antivirals may act in a cell line-specific manner. Recently, we have described novel pyridyl indole esters and peptidomimetics as potent inhibitors of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) main protease. Here, we analysed the impact of these compounds on viral replication. It has been shown that some antivirals against SARS-CoV-2 act in a cell line-specific way. Thus, the compounds were tested in Vero, Huh-7, and Calu-3 cells. We showed that the protease inhibitors at 30 µM suppress viral replication by up to 5 orders of magnitude in Huh-7 cells, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates inhibited viral replication in all cell lines, indicating that they might repress viral replication in human tissue as well. Thus, we investigated three compounds in human precision-cut lung slices and observed donor-dependent antiviral activity in this patient-near system. Our results provide evidence that even direct-acting antivirals may act in a cell line-specific manner.
Audience	Academic
Author	Sewald, Katherina Müller, Christa E. König, Eva-Maria Breidenbach, Julian Geiger, Nina Roll, Valeria Bodem, Jochen Diesendorf, Viktoria Pillaiyar, Thanigaimalai Obernolte, Helena Gütschow, Michael
AuthorAffiliation	3 Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry University of Bonn, An der Immenburg 4, 53121 Bonn, Germany 1 Institute for Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany 2 Member of DZL, BREATH and iCAIR, 30625 Hannover, Germany
AuthorAffiliation_xml	– name: 3 Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry University of Bonn, An der Immenburg 4, 53121 Bonn, Germany – name: 2 Member of DZL, BREATH and iCAIR, 30625 Hannover, Germany – name: 1 Institute for Virology and Immunobiology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany
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SubjectTerms	Analysis Antiviral drugs Cell culture Cell growth Communication Coronaviruses Cytotoxicity Enzymes Genomes Health aspects Hepatitis C HIV Human immunodeficiency virus Immunization Infections Patients Protease inhibitors Proteases Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Viruses
Title	Cell Type-Specific Anti-Viral Effects of Novel SARS-CoV-2 Main Protease Inhibitors
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