Repurposing Astragalus Polysaccharide PG2 for Inhibiting ACE2 and SARS-CoV-2 Spike Syncytial Formation and Anti-Inflammatory Effects

Viruses. 2023 Feb 27;15(3):641. doi: 10.3390/v15030641.

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health. In an effort to develop novel anti-coronavirus therapeutics and achieve prophylactics, we used gene set enrichment analysis (GSEA) for drug screening and identified that Astragalus polysaccharide (PG2), a mixture of polysaccharides purified from Astragalus membranaceus, could effectively reverse COVID-19 signature genes. Further biological assays revealed that PG2 could prevent the fusion of BHK21-expressing wild-type (WT) viral spike (S) protein and Calu-3-expressing ACE2. Additionally, it specifically prevents the binding of recombinant viral S of WT, alpha, and beta strains to ACE2 receptor in our non-cell-based system. In addition, PG2 enhances let-7a, miR-146a, and miR-148b expression levels in the lung epithelial cells. These findings speculate that PG2 has the potential to reduce viral replication in lung and cytokine storm via these PG2-induced miRNAs. Furthermore, macrophage activation is one of the primary issues leading to the complicated condition of COVID-19 patients, and our results revealed that PG2 could regulate the activation of macrophages by promoting the polarization of THP-1-derived macrophages into an anti-inflammatory phenotype. In this study, PG2 stimulated M2 macrophage activation and increased the expression levels of anti-inflammatory cytokines IL-10 and IL-1RN. Additionally, PG2 was recently used to treat patients with severe COVID-19 symptoms by reducing the neutrophil-to-lymphocyte ratio (NLR). Therefore, our data suggest that PG2, a repurposed drug, possesses the potential to prevent WT SARS-CoV-2 S-mediated syncytia formation with the host cells; it also inhibits the binding of S proteins of WT, alpha, and beta strains to the recombinant ACE2 and halts severe COVID-19 development by regulating the polarization of macrophages to M2 cells.

Keywords: COVID-19; cytokine storm; macrophages; microRNAs; viral entry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2* / metabolism
  • Anti-Inflammatory Agents / pharmacology
  • Astragalus propinquus / chemistry
  • COVID-19*
  • Drug Repositioning
  • Humans
  • MicroRNAs
  • Polysaccharides* / pharmacology
  • SARS-CoV-2 / metabolism
  • Spike Glycoprotein, Coronavirus* / metabolism

Substances

  • Angiotensin-Converting Enzyme 2
  • Anti-Inflammatory Agents
  • MicroRNAs
  • Polysaccharides
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2

Grants and funding

The study was supported by grants from the Ministry of Science and Technology, Taiwan, to Y.-H.P. (MOST 109-2327-B-400-004 and MOST 109-2320-B-010-034-MY3), RJ.-M.L. (MOST 110-2320-B-030-008- and MOST 111-2320-B-030-008-), and C.-Y.F.H. (MOST 110-2320-B-A49A-541-, MOST111-2321-B-A49-007-, and MOST 111-2320-B-A49-036-); by a grant from the National Yang Ming Chiao Tung University—Far Eastern Memorial Hospital Joint Research Program (111DN03) to Y.-H.P.; and by grants from the National Science and Technology Council (MOST 111-2320-B-077-002-MY3) to H.-K.L.