Host-directed iminosugars MON-DNJ and NB-DNJ inhibit measles virus and human respiratory syncytial virus replication in vitro.

Measles virus (MeV) and human respiratory syncytial virus (HRSV) remain significant causes of global morbidity and mortality; measles in unvaccinated children, HRSV in infants below 6 months, immunocompromised, and the elderly. Despite the availability of vaccines and prophylactic monoclonal antibodies, there is a need for novel antiviral therapeutics. Both MeV and HRSV depend on correct glycosylation of surface glycoproteins (F and H for MeV, F and G for HRSV) for receptor interaction, entry, fusion, and cell-to-cell spread. Host endoplasmic reticulum (ER) α-glucosidases enable the proper folding of these N-linked viral enveloped glycoproteins via the calnexin pathway. Therefore, targeting those host-enzymes offers a promising broad-spectrum antiviral strategy. Here we demonstrate that the iminosugars MON-DNJ and NB-DNJ, which are inhibitors of ER α-glucosidases I and II, exert antiviral activity against both MeV and HRSV in vitro using different treatment protocols. Both compounds reduced viral spread as measured by infected cell surface area, decreased viral titers, and, in the case of HRSV, preserved cell viability in a dose-dependent manner. Gene set enrichment analysis of MeV and HRSV infection datasets revealed specific enrichment of MON-DNJ-modulated gene set, suggesting overlap in host transcriptional response. Antiviral activity to HRSV was confirmed in human airway organoids. These findings support the further development of iminosugars as host-directed antivirals against MeV and HRSV.