High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1
The Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) has continuously evolved, resulting in the emergence of several variants of concern (VOCs). To study mechanisms of viral entry and potentially identify specific inhibitors, we pseudotyped lentiviral vectors with different SARS-CoV...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222004930 |
| _version_ | 1811336546593275904 |
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| author | Maria Kuzikov Jannis Woens Andrea Zaliani Julia Hambach Thomas Eden Boris Fehse Bernhard Ellinger Kristoffer Riecken |
| author_facet | Maria Kuzikov Jannis Woens Andrea Zaliani Julia Hambach Thomas Eden Boris Fehse Bernhard Ellinger Kristoffer Riecken |
| author_sort | Maria Kuzikov |
| collection | DOAJ |
| description | The Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) has continuously evolved, resulting in the emergence of several variants of concern (VOCs). To study mechanisms of viral entry and potentially identify specific inhibitors, we pseudotyped lentiviral vectors with different SARS-CoV-2 VOC spike variants (D614G, Alpha, Beta, Delta, Omicron/BA.1), responsible for receptor binding and membrane fusion. These SARS-CoV-2 lentiviral pseudoviruses were applied to screen 774 FDA-approved drugs. For the assay we decided to use CaCo2 cells, since they equally allow cell entry through both the direct membrane fusion pathway mediated by TMPRSS2 and the endocytosis pathway mediated by cathepsin-L. The active molecules which showed stronger differences in their potency to inhibit certain SARS-CoV-2 VOCs included antagonists of G-protein coupled receptors, like phenothiazine-derived antipsychotic compounds such as Chlorpromazine, with highest activity against the Omicron pseudovirus. In general, our data showed that the various VOCs differ in their preferences for cell entry, and we were able to identify synergistic combinations of inhibitors. Notably, Omicron singled out by relying primarily on the endocytosis pathway while Delta preferred cell entry via membrane fusion. In conclusion, our data provide new insights into different entry preferences of SARS-CoV-2 VOCs, which might help to identify new drug targets. |
| first_indexed | 2024-04-13T17:41:03Z |
| format | Article |
| id | doaj.art-f3170e490eda452d91c6a3a57f93f096 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-13T17:41:03Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-f3170e490eda452d91c6a3a57f93f0962022-12-22T02:37:11ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-07-01151113104High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1Maria Kuzikov0Jannis Woens1Andrea Zaliani2Julia Hambach3Thomas Eden4Boris Fehse5Bernhard Ellinger6Kristoffer Riecken7Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; Department of Life Sciences and Chemistry, Jacobs University Bremen, 28759 Bremen, GermanyResearch Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, GermanyInstitute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyInstitute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyResearch Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 20246 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; Corresponding author at: Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Schnackenburgallee 114, 22525 Hamburg, Germany.Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Correspondence to: Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.The Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) has continuously evolved, resulting in the emergence of several variants of concern (VOCs). To study mechanisms of viral entry and potentially identify specific inhibitors, we pseudotyped lentiviral vectors with different SARS-CoV-2 VOC spike variants (D614G, Alpha, Beta, Delta, Omicron/BA.1), responsible for receptor binding and membrane fusion. These SARS-CoV-2 lentiviral pseudoviruses were applied to screen 774 FDA-approved drugs. For the assay we decided to use CaCo2 cells, since they equally allow cell entry through both the direct membrane fusion pathway mediated by TMPRSS2 and the endocytosis pathway mediated by cathepsin-L. The active molecules which showed stronger differences in their potency to inhibit certain SARS-CoV-2 VOCs included antagonists of G-protein coupled receptors, like phenothiazine-derived antipsychotic compounds such as Chlorpromazine, with highest activity against the Omicron pseudovirus. In general, our data showed that the various VOCs differ in their preferences for cell entry, and we were able to identify synergistic combinations of inhibitors. Notably, Omicron singled out by relying primarily on the endocytosis pathway while Delta preferred cell entry via membrane fusion. In conclusion, our data provide new insights into different entry preferences of SARS-CoV-2 VOCs, which might help to identify new drug targets.http://www.sciencedirect.com/science/article/pii/S0753332222004930SARS-CoV-2PseudovirusLentiviral vectorVariant of concernD614GDelta |
| spellingShingle | Maria Kuzikov Jannis Woens Andrea Zaliani Julia Hambach Thomas Eden Boris Fehse Bernhard Ellinger Kristoffer Riecken High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1 Biomedicine & Pharmacotherapy SARS-CoV-2 Pseudovirus Lentiviral vector Variant of concern D614G Delta |
| title | High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1 |
| title_full | High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1 |
| title_fullStr | High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1 |
| title_full_unstemmed | High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1 |
| title_short | High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1 |
| title_sort | high throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of sars cov 2 delta and omicron ba 1 |
| topic | SARS-CoV-2 Pseudovirus Lentiviral vector Variant of concern D614G Delta |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222004930 |
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