Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV‑2

Herein, we report the synthesis and biological evaluation
of a
novel series of heparinoid amphiphiles as inhibitors of heparanase
and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library
of highly sulfated homo-oligosaccharides bearing d-glucose
or a C5-epimer (i.e., l-idose or l-iduronic acid)
conjugated with various lipophilic groups was synthesized and investigated
for antiviral activity. Sulfated higher oligosaccharides of d-glucose or l-idose with lipophilic aglycones displayed
potent anti-SARS-CoV-2 and antiheparanse activity, similar to or better
than pixatimod (PG545), and were more potent than their isosteric l-iduronic acid congeners. Lipophilic groups such as cholestanol
and C18-aliphatic substitution are more advantageous than
functional group appended lipophilic moieties. These findings confirm
that fine-tuning of higher oligosaccharides, degree of sulfation,
and lipophilic groups can yield compounds with potent anti-SARS-CoV-2
activity.