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Cell Rep. 2017 Dec 12;21(11):3032-3039. doi: 10.1016/j.celrep.2017.11.054.

A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity.

Author information

1
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
2
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06511, USA.
3
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06511, USA; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06511, USA.
4
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: carette@stanford.edu.

Abstract

The mosquito-borne flaviviruses include important human pathogens such as dengue, Zika, West Nile, and yellow fever viruses, which pose a serious threat for global health. Recent genetic screens identified endoplasmic reticulum (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors. Here, we show that a chemical modulator of the OST complex termed NGI-1 has promising antiviral activity against flavivirus infections. We demonstrate that NGI-1 blocks viral RNA replication and that antiviral activity does not depend on inhibition of the N-glycosylation function of the OST. Viral mutants adapted to replicate in cells deficient of the OST complex showed resistance to NGI-1 treatment, reinforcing the on-target activity of NGI-1. Lastly, we show that NGI-1 also has strong antiviral activity in primary and disease-relevant cell types. This study provides an example for advancing from the identification of genetic determinants of infection to a host-directed antiviral compound with broad activity against flaviviruses.

KEYWORDS:

West Nile virus; Zika virus; antiviral; dengue virus; flaviviruses; host-directed therapy; oligosaccharyltransferase; yellow fever virus

PMID:
29241533
PMCID:
PMC5734657
DOI:
10.1016/j.celrep.2017.11.054
[Indexed for MEDLINE]
Free PMC Article

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