PMC:7499584 / 1258-9052 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7499584","sourcedb":"PMC","sourceid":"7499584","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7499584","text":"Previously reported efficacy of antiviral activities\nCopious literature suggests that glycosylation inhibitors are potent antivirals for enveloped viruses with a coat or spike protein. In the 1970s and 1980s, a number of investigators examined interference with glycan synthesis on viral coat proteins as a mode for viral inhibition. Compans showed in 1971, D-glucosamine and 2-deoxy-D-glucose inhibited glycoprotein maturation in Sindbis virus (Compans 1971). Several other studies used these two compounds for inhibition of Semliki Forest virus (Kaluza et al. 1972), enveloped RNA viruses (Kaluza et al. 1973), Influenza (Klenk et al. 1972), VSV, Newcastle disease (Scholtissek et al. 1974) and enveloped viruses in general (Scholtissek et al. 1975). In 1973, Okayama et al. showed that ß-xylosides could stimulate free GAG chains and inhibit GAG formation on proteoglycan core proteins (Okayama et al. 1973). Later, a number of researchers showed that GAGs were important as cellular receptors in HSV and HCV and that ß-xylosides could inhibit viral infectivity by sidetracking GAG synthesis to soluble saccharides (see below).\nSchwartz reported, in 1974, tunicamycin inhibition of glycosylation of influenza virus hemagglutinin (Schwartz et al. 1974) and in 1976 showed that tunicamycin, which inhibits the formation of N-acetylglucosamine-lipid intermediates in N-linked glycan synthesis (Lennarz 1975), suppressed glycoprotein synthesis in Semliki Forest, influenza and avian sarcoma virus (Schwarz et al. 1976). Kornfeld et al. (1977) examined the effect of tunicamycin (Leavitt et al. 1977a) on growth of Sindbis and VSV in BHK cells and found at 500 ng/ml, 99.9% inhibition of replication without detection of non-infectious particles (Leavitt et al. 1977b). Viral proteins were synthesized, but glycoproteins were under-glycosylated (Leavitt et al. 1977b) and temperature sensitive (Gibson et al. 1979). Their conclusion was that in enveloped viruses, glycosylation was essential for normal viral particle assembly. Morrison et al. (1978) found that tunicamycin had no effect on glycoprotein attachment to intracellular membranes or protein transport to the endoplasmic reticulum lumen, but instead prevented glycoprotein migration from the rough to smooth. Kornfeld et al. (1979) found that VSV non-glycosylated glycoprotein underwent intracellular aggregation upon tunicamycin treatment (Gibson et al. 1979), an indication of improper folding or exposure of hydrophobic peptide due to pauciglycosylation. Diggelman (1979) showed biosynthesis of an unglycosylated envelope glycoprotein of Rous sarcoma virus in the presence of tunicamycin. Pizer et al. (1980) showed that tunicamycin inhibited production of infectious herpes simplex virus-1 (HSV1). Blocking addition of carbohydrate to glycoprotein precursors with tunicamycin resulted in disappearance of proteins, postulated due to degradation of unglycosylated polypeptides. They concluded that the glycans either stabilize the envelope proteins or provide proper structure for processing of the proteins necessary for infectivity. Stallcup and Fields (1981) inhibited measles virus with tunicamycin (24).\nHolmes et al. (1981) showed that a corona virus, mouse hepatitis virus, MHV, had a glycoprotein E1 glycosylated normally in the presence of tunicamycin. This indicated that E1 bore O-linked instead of N-linked glycans. The “peplomeric glycoprotein E2 was not detectable upon tunicamycin treatment,” indicating its synthesis was interdicted or its degradation was facilitated by lack of N-linked glycosylation and was improperly processed (Holmes et al. 1981). E2 may be analogous to the S-spike glycoprotein. Viral particles were produced with tunicamycin treatment but were noninfective, lacking E2, which was required for attachment to viral receptors on cells, probably analogous ACE2 by today’s knowledge. At that time, no drug was known to inhibit O-glycosylation, such as α-benzyl-GalNAc, in use today. Because of these observations, either N-linked or O-linked glycosylation interference may potentially interdict SARS-Cov2 infectivity.\nTunicamycin was employed in antiviral tests and was very effective, but it was considered too toxic by most investigators to be developed as a drug at the concentrations used. However, Banerjee et al. (2011), in cancer treatment, found a safe concentration of a purified tunicamycin and dosage in mice (250 μg/kg oral twice a week for 4 weeks) that inhibited MDA-MB0231 triple negative breast-cancer tumor formation in live mice, without overt toxicity and involved the unfolded protein response. Nanoformulations were effective (Banerjee et al. 2013). Recent articles define the detailed basis for tunicamycin’s activity (Hakulinen et al. 2017; Yoo et al. 2018). Tunicamycins should be tested now for infectivity assays with SARS COV2 alone or in combinations with other inhibitors.\nElbein et al. (1982) showed swainsonine, an α-mannosidase inhibitor, to inhibit processing of oligosaccharides on influenza viral hemagglutinin, and in 1983 showed its effect on vesicular stomatitis virus (Kang and Elbein 1983). In 1983, he showed castanospermine, an α-glucosidase inhibitor, inhibited influenza hemagglutinin expression (Pan et al. 1983). Both inhibited N-glycan processing. Tyms et al. (1987) showed castanospermine and other plant alkaloid glucosidase inhibitors to block HIV growth. Sunkara et al. (1987) tested castanospermine and 1-deoxynojirimycin (Duvoglustat) showing anti-retroviral activity. Dwek et al. (1998) later suggested α-glucosidase inhibitors as general antiviral agents (Mehta et al. 1998). Chapel et al. (2006) showed antiviral effects of α-glucosidase inhibitors on hepatitis C virus. Chang et al. (2013a) reported that iminosugar α-glucosidase inhibitors related to 1-deoxynojirimycin (that interfered with N-linked glycan maturation in the calnexin-mediated folding pathway) were also effective as antivirals for Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae including hemorrhagic fever Marburg and Ebola in mice. 1-Deoxynojirimycin (Duvoglustat) suppresses postprandial blood glucose and is used for treatment of diabetics in doses of 20-110 mg/kg (Gao et al. 2016, Tong et al. 2018). Qu et al. (2011), inhibitors of endoplasmic reticulum α-glucosidases potently suppress hepatitis C virus virion assembly and release. Howe et al. (2013) applied similar compounds to HCV and BVDV. Castanospermine and its O- and N-butyl derivatives were tested in many viral systems with positive results and FDA approval for type 2 diabetes and Gaucher’s treatments as described below. Off-label, repurposing treatments for COVID19 should be considered.\nCelgosivir (6-O-butanoyl castanospermine), an approved α-glucosidase inhibitor drug for type 2 diabetes and Gaucher’s disease, inhibits all four Dengue, DENV serotypes (Sayce et al. 2010; Rathore et al. 2011). “Fluorescence microscopy showed that the antiviral mechanism of Celgosivir, is in part, due to misfolding and accumulation of DENV non-structural protein 1 (NS1) in the endoplasmic reticulum” (Lachmann 2003). Moreover, Celgosivir modulates the host’s unfolded protein response (UPR) for its antiviral action. Significantly, Celgosivir is effective in lethal challenge mouse models that recapitulate primary or secondary antibody-dependent enhanced DENV infection. Celgosivir-treated mice showed enhanced survival, reduced viremia and robust immune response, as reflected by serum cytokine analysis. Importantly, survival increased even after treatment was delayed till 2 days post-infection.” (Rathore et al. 2011). Together, this suggests that Celgosivir, which has been clinically determined to be safe in humans, may be a valuable candidate for clinical testing in COVID19 patients. 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