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

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.

Authors+Show Affiliations

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos #05-01, 138670 Singapore, Singapore.

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Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.

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Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos #05-01, 138670 Singapore, Singapore.

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Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos #05-01, 138670 Singapore, Singapore.

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Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos #05-01, 138670 Singapore, Singapore.

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

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Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

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Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.

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Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland.

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Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos #05-01, 138670 Singapore, Singapore. Electronic address: bonamgh1@gmail.com.

Novartis Institutes for BioMedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, 4056 Basel, Switzerland; Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland. Electronic address: dominic.hoepfner@novartis.com.

Source

Cell reports 19:3 2017 Apr 18 pg 451-460

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28423309