SARS-CoV-2 variant-specific enhancement of dendritic heparan sulfate mimetic antiviral activities.

SARS-CoV-2 continues to impose a substantial burden to healthcare systems, economies, and communities. While several antivirals are approved for COVID-19 treatment, their use is limited by contraindications and uptake, and vaccines provide only partial and waning protection against infection. Therefore, additional antivirals are urgently needed to combat SARS-CoV-2. This study evaluated dendritic heparan sulfate (HS) mimetics as antivirals using pseudoviruses and wildtype SARS-CoV-2 spanning different lineages. Using immunofluorescence and plaque reduction assays, we identified HS mimetics that potently inhibited the Omicron BA.1 variant (IC50 values 0.74 - 15.26 μM) with no impacts on cell viability up to 200 μM. One mimetic, Tet-ST-12 demonstrated nanomolar inhibition of the Omicron BA.1 subvariant, however all test compounds had reduced antiviral efficacy against ancestral variants of SARS-CoV-2 (Wuhan D614G, Mu and Delta, IC50 values > 100 μM). These findings highlighted the variant-specific differences in HS mimetics' binding affinities and showcase their potential for development as antivirals against SARS-CoV-2. Furthermore, an examination of the direct-acting antiviral nirmatrelvir in combination with Tet-ST-12 revealed strong synergy (Bliss score >20), enabling significant dose reductions to achieve similar inhibition of Omicron BA.1 infectivity, while raising the barrier to the evolution of antiviral resistance. This study demonstrates the potential for the dendritic HS mimetics as antiviral candidates against SARS-CoV-2 and its evolving variants.