Your browser doesn't support javascript.
High-throughput drug screening allowed identification of entry inhibitors specifically targeting different routes of SARS-CoV-2 Delta and Omicron/BA.1.
Kuzikov, Maria; Woens, Jannis; Zaliani, Andrea; Hambach, Julia; Eden, Thomas; Fehse, Boris; Ellinger, Bernhard; Riecken, Kristoffer.
  • Kuzikov M; Fraunhofer 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 Universi
  • Woens J; Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Zaliani A; Fraunhofer 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.
  • Hambach J; Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Eden T; Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Fehse B; Research 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, Germany.
  • Ellinger B; Fraunhofer 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. Electronic address: bernhard.ellinger@itmp.fraunhofer.de.
  • Riecken K; Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: k.riecken@uke.uni-hamburg.de.
Biomed Pharmacother ; 151: 113104, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1850705
ABSTRACT
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Traditional medicine / Variants Limits: Humans Language: English Journal: Biomed Pharmacother Year: 2022 Document Type: Article

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Traditional medicine / Variants Limits: Humans Language: English Journal: Biomed Pharmacother Year: 2022 Document Type: Article