Targeting STT3A‐oligosaccharyltransferase with NGI‐1 causes herpes simplex virus 1 dysfunction

Herpes simplex virus 1 (HSV‐1) is a contagious neurotropic herpesvirus responsible for oral lesions and herpesviral encephalitis. The HSV‐1 envelope contains N ‐glycosylated proteins involved in infection and that are candidate drug targets. NGI‐1 is a small‐molecule inhibitor of oligosaccharyltransferase (OST) complexes STT3A‐OST and STT3B‐OST, which catalyze cotranslational and post‐translational N ‐glycosylation, respectively. Because host OSTs attach HSV‐1 glycans, NGI‐1 might have anti–HSV‐1 activity. We evaluated HSV‐1 function using NGI‐1 and human embryonic kidney 293 knockout lines for OST isoform‐specific catalytic and accessory subunits. N ‐glycosylation of 2 representative envelope proteins (gC and gD) was primarily dependent upon STT3A‐OST, but to a large extent replaceable by STT3B‐OST. Knockouts impairing STT3A‐ or STT3B‐OST activity, by themselves, did not appreciably affect HSV‐1 function (plaque‐forming units, normalized to viral particles measured by unglycosylated capsid protein VP5 content). However, with cells lacking STT3B‐OST activity (missing the catalytic subunit STT3B or the oxidoreductase subunits magnesium transporter 1/tumor suppressor candidate 3) and thus solely dependent upon STT3A‐OST for N ‐glycosylation, NGI‐1 treatment resulted in HSV‐1 having cell type–dependent dysfunction (affecting infectivity with Vero cells much more than with the 293 lines). Ablation of post‐translational N ‐glycosylation can therefore make HSV‐1 infectivity, and possibly masking of immunogenic peptide epitopes by glycans, highly sensitive to pharmacological inhibition of cotranslational N ‐glycosylation.—Lu, H., Cherepanova, N. A., Gilmore, R., Contessa, J. N., Lehrman, M. A. Targeting STT3A‐oligosaccharyltransferase with NGI‐1 causes herpes simplex virus 1 dysfunction. FASEB J. 33, 6801–6812 (2019). www.fasebj.org