COVID-19, caused by the SARS-CoV-2 virus, has now spread worldwide with catastrophic human and economic impacts and currently has infected over 10 million people and killed over 500,000¹. In an effort to mitigate disease symptoms and impede viral spread, efforts in vaccine development and drug discovery are being conducted at a rapid pace². Recently, we showed that the well-known anticoagulant heparin has exceptional binding affinity to the spike protein (S-protein) of SARS-CoV-2³. The S-protein of SARS-CoV-2 bound more tightly to immobilized heparin (K_D = ~10⁻¹¹ M) than the S-proteins of either SARS-CoV (K_D = ~10⁻⁷ M) or MERS-CoV (K_D = ~10^-9 M). However, it is not known whether the tight binding of heparin to the SARS-CoV-2 S-protein translates into potent antiviral activity. In the current study, we evaluated the in vitro antiviral properties of heparin and other closely related polysaccharides to assess the relevance of heparin-related GAGs and other sulfated polysaccharides as part of the pharmacopeia of potential therapeutics that target SARS-CoV-2. Vero-CCL81, which expresses both ACE2 and TMPRSS2⁴, were used for viral replication at high titer5 for use in antiviral assays.