A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity

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. The mosquito-borne flaviviruses depend on oligosaccharyltransferase (OST) for replication. Puschnik et al. reveal that the OST inhibitor NGI-1 has pan-flaviviral activity in several disease-relevant cell types. The effect on viral replication acts through OST but appears to be largely independent of blocking catalytic N-glycosylation activity.