Antiviral strategies should focus on stimulating the biosynthesis of heparan sulfates, not their inhibition.

Antiviral strategies for viruses that utilize proteoglycan core proteins (syndecans and glypicans) as receptors should focus on heparan sulfate (HS) biosynthesis rather than on inhibition of these sugar chains. Here, we show that heparin and certain xylosides, which exhibit in vitro viral entry inhibitory properties against HSV-1, HSV-2, HPV-16, HPV-31, HVB, HVC, HIV-1, HTLV-1, SARS-CoV-2, HCMV, DENV-1, and DENV-2, stimulated HS biosynthesis at the cell surface 2- to 3-fold for heparin and up to 10-fold for such xylosides. This is consistent with the hypothesis from a previous study that for core protein attachment, viruses are glycosylated at HS attachment sites (i.e., serine residues intended to receive the D-xylose molecule for initiating HS chains). Heparanase overexpression, endocytic entry, and syndecan shedding enhancement, all of which are observed during viral infection, lead to glycocalyx deregulation and appear to be direct consequences of this hypothesis. In addition to the appearance of type 2 diabetes and the degradation of HS observed during viral infection, we linked this hypothesis to that proposed in a previous publication.