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The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase

Estoppey, David and Lee, Chia Min and Janoschke, Marco and Mathys, Philippe and Filipuzzi, Ireos and Schuhmann, Tim and Riedl, Ralph and Aust, Thomas and Galuba, Olaf and Mcallister, Gregory and Russ, Carsten and Spiess, Martin and Bouwmeester, Antonius and Bonamy, Ghislain and Hoepfner, Dominic (2017) The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase. Cell Reports, 19 (3). pp. 451-460. ISSN 22111247

Abstract

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.

Item Type: Article
Keywords: cavinafungin chemogenomic profiling CRISPR/Cas9 dengue virus SEC11 SEC11A signal peptidase Zika virus
Date Deposited: 23 May 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/30138

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