The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase
| Autor: | Chia Min Lee, Kah Fei Wan, Ralph Riedl, Marco Janoschke, Ghislain M. C. Bonamy, Tewis Bouwmeester, Olaf Galuba, Hongping Dong, Philippe Mathys, Tim Schuhmann, David Estoppey, Martin Spiess, Carsten Russ, Dominic Hoepfner, Ireos Filipuzzi, Boon Heng Lee, Gregory McAllister, Thomas Aust |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Signal peptide Protein subunit 030106 microbiology Saccharomyces cerevisiae Dengue virus medicine.disease_cause Virus Replication General Biochemistry Genetics and Molecular Biology Zika virus 03 medical and health sciences Lipopeptides Viral Proteins medicine CRISPR Humans Flavivirus Infections lcsh:QH301-705.5 Signal peptidase Biological Products biology Cas9 Genome Human Serine Endopeptidases Membrane Proteins Genomics Zika Virus Dengue Virus biology.organism_classification HCT116 Cells Virology Protein Subunits 030104 developmental biology lcsh:Biology (General) Gene Knockdown Techniques CRISPR-Cas Systems |
| Zdroj: | Cell Reports, Vol 19, Iss 3, Pp 451-460 (2017) |
| ISSN: | 2211-1247 |
| Popis: | Summary: Flavivirus infections by Zika and dengue virus impose a significant global healthcare threat with no US Food and Drug Administration (FDA)-approved vaccination or specific antiviral treatment available. Here, we present the discovery of an anti-flaviviral natural product named cavinafungin. Cavinafungin is a potent and selectively active compound against Zika and all four dengue virus serotypes. Unbiased, genome-wide genomic profiling in human cells using a novel CRISPR/Cas9 protocol identified the endoplasmic-reticulum-localized signal peptidase as the efficacy target of cavinafungin. Orthogonal profiling in S. cerevisiae followed by the selection of resistant mutants pinpointed the catalytic subunit of the signal peptidase SEC11 as the evolutionary conserved target. Biochemical analysis confirmed a rapid block of signal sequence cleavage of both host and viral proteins by cavinafungin. This study provides an effective compound against the eukaryotic signal peptidase and independent confirmation of the recently identified critical role of the signal peptidase in the replicative cycle of flaviviruses. : Recent outbreaks and lack of effective treatments against dengue and Zika virus have caused public concerns. Estoppey et al. have identified cavinafungin as exerting potent and selective antiviral activity by targeting the signal-binding cleft of the catalytic subunit of the endoplasmic reticulum signal peptidase. Keywords: Zika virus, dengue virus, cavinafungin, signal peptidase, SEC11A, SEC11, CRISPR/Cas9, chemogenomic profiling |
| Databáze: | OpenAIRE |
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