Glucosidase inhibitors suppress SARS-CoV-2 in tissue culture and may potentiate

Abstract

ABSTRACTIminosugar glucosidase inhibitors prevent the folding of a range of viral N-linked glycoproteins, ranging from hepatitis B to Ebola. We recently showed they inhibit folding and function of the ACE2 protein, which is the receptor for SARS-CoV-2, and they have also inhibited the SARS Spike polypeptides. Here we report that the imino sugar glucosidase inhibitors, N-butyl deoxynojirimycin (NBDNJ), which is approved for management of lysosomal storage disease (sold as Zavesca), and ureido-N-hexyl deoxynojirimycine (BSBI-19029), suppress the replication of SARS-ncCoV-2/USA/WA1/2020 strain, in tissue culture. Moreover, combinations of either of these iminosugars with Remdesivir were particularly potent in suppressing SARS-CoV-2. Briefly, NBDNJ, 19029 and Remdesivir suppressed SARS-CoV-2 production in A549ACE2 human lung cells with IC90s of ~130 μM, ~4.0 μM, and 0.006 μM respectively. The combination of as little as 0.037 μM of NBDNJ or 0.04 μM 19029, respectively and 0.002 μM Remdesivir yielded IC90s. Medical strategies to manage SARS-CoV-2 infection of people are urgently needed, and although Remdesivir and Favipiravir have shown efficacy, it is limited. NBDNJ was recently reported by others to have tissue culture activity against SARS-CoV-2, so our report confirms this, and extends the findings to a more potent iminosugar, 19029 and combination with Remdesivir. Since both NBDNJ and Remdesivir are both approved and available for human use, the possibility that NBDNJ has mono therapeutic value against SARS-CoV-2 as well as can enhance Remdesivir, may have clinical implications, which are discussed, here.