A Heparan Sulfate Mimetic RAFT Copolymer Inhibits SARS‐CoV‐2 Infection and Ameliorates Viral‐Induced Inflammation

Abstract The high transmissibility and mutation ability of coronaviruses enable them to easily escape existing immune protection and also pose a challenge to existing antiviral drugs. Moreover, drugs only targeting viruses cannot always attenuate the “cytokine storm”. Herein, a synthetic heparan sulfate (HS) mimetic, HMSA‐06 is reported, that exhibited antiviral activities against both the SARS‐CoV‐2 prototype and Omicron strains by targeting viral entry and replication. Of particular note, HMSA‐06 demonstrated more potent anti‐SARS‐CoV‐2 effects than PG545 and Roneparstat. SARS‐CoV‐2 is reported to hijack autophagy to facilitate its replication, therefore boosting autophagy can attenuate SARS‐CoV‐2 infection. It is revealed that HMSA‐06, but not a similar HS mimetic that failed to inhibit SARS‐CoV‐2, can upregulate cellular autophagy flux. In addition, HMSA‐06 was found to robustly block the NLRP3‐mediated inflammatory reaction in SARS‐CoV‐2 infected THP‐1 derived macrophages as evidenced by a reduction in inflammasome formation and the subsequent decreased secretion of mature caspase‐1 and IL‐1β. The HMSA‐06's inflammation inhibitory function is further confirmed using a LPS/ATP‐stimulated THP‐1 macrophage model. Altogether, this study has identified a promising HS mimetic to combat SARS‐CoV‐2‐associated diseases by inhibiting viral infection and attenuating viral‐induced inflammatory reaction, providing insights into the development of novel anti‐coronavirus drugs in the future.