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 (KD = ~10−11 M) than the S-proteins of either SARS-CoV (KD = ~10−7 M) or MERS-CoV (KD = ~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.