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

• Published in: Cell reports (Cambridge) Vol. 19; no. 3; pp. 451 - 460
• Main Authors: Estoppey, David, Lee, Chia Min, Janoschke, Marco, Lee, Boon Heng, Wan, Kah Fei, Dong, Hongping, Mathys, Philippe, Filipuzzi, Ireos, Schuhmann, Tim, Riedl, Ralph, Aust, Thomas, Galuba, Olaf, McAllister, Gregory, Russ, Carsten, Spiess, Martin, Bouwmeester, Tewis, Bonamy, Ghislain M.C., Hoepfner, Dominic
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-04-2017; Elsevier
• Subjects: Biological Products - chemistry; Biological Products - pharmacology; cavinafungin; chemogenomic profiling; CRISPR-Cas Systems - genetics; CRISPR/Cas9; dengue virus; Dengue Virus - drug effects; Dengue Virus - physiology; Gene Knockdown Techniques; Genome, Human; Genomics; HCT116 Cells; Humans; Lipopeptides - chemistry; Lipopeptides - pharmacology; Membrane Proteins; Protein Subunits - metabolism; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; SEC11; SEC11A; Serine Endopeptidases; signal peptidase; Viral Proteins - metabolism; Virus Replication - drug effects; Zika virus; Zika Virus - drug effects; Zika Virus - physiology; SEC11; CRISPR/Cas9; signal peptidase; dengue virus; cavinafungin; Zika virus; chemogenomic profiling; SEC11A
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.03.071

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.
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•Cavinafungin has potent and selective antiviral activity•CRISPR/Cas9 profiling identifies the ER signal peptidase as the target of cavinafungin•Resistance profiling maps the putative binding site of cavinafungin on SEC11•Biochemical assays validate cavinafungin inhibition of viral and host protein processing
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.