The SARS-CoV-2 pandemic highlighted the need for broad-spectrum antivirals to increase our preparedness. Patients often require treatment by the time that blocking virus replication is less effective. Therefore, therapy should not only aim to inhibit the virus, but also to suppress pathogenic host responses, e.g., leading to microvascular changes and pulmonary damage. Clinical studies have previously linked SARS-CoV-2 infection to pathogenic intussusceptive angiogenesis in the lungs, involving the upregulation of angiogenic factors such as ANGPTL4. The β-blocker propranolol is used to suppress aberrant ANGPTL4 expression in the treatment of hemangiomas. Therefore, we investigated the effect of propranolol on SARS-CoV-2 infection and the expression of ANGPTL4. SARS-CoV-2 upregulated ANGPTL4 in endothelial and other cells, which could be suppressed with R-propranolol. The compound also inhibited the replication of SARS-CoV-2 in Vero-E6 cells and reduced the viral load by up to ~2 logs in various cell lines and primary human airway epithelial cultures. R-propranolol was as effective as S-propranolol but lacks the latter’s undesired β-blocker activity. R-propranolol also inhibited SARS-CoV and MERS-CoV. It inhibited a post-entry step of the replication cycle, likely via host factors. The broad-spectrum antiviral effect and suppression of factors involved in pathogenic angiogenesis make R-propranolol an interesting molecule to further explore for the treatment of coronavirus infections.
SARS-CoV-2 emerged in 2019 and since its global spread has caused the death of over 6 million people. There are currently few antiviral options for treatment of COVID-19. Repurposing of known drugs can be a fast route to obtain molecules that inhibit viral infection and/or modulate pathogenic host responses. Honokiol is a small molecule from Magnolia trees, for which several biological effects have been reported, including anticancer and anti-inflammatory activity. Honokiol has also been shown to inhibit several viruses in cell culture. In this study, we show that honokiol protected Vero E6 cells from SARS-CoV-2-mediated cytopathic effect with an EC50 of 7.8 µM. In viral load reduction assays we observed that honokiol decreased viral RNA copies as well as viral infectious progeny titers. The compound also inhibited SARS-CoV-2 replication in the more relevant A549 cells, expressing ACE2 and TMPRSS2. A time-of-addition assay showed that honokiol inhibited virus replication even when added post infection, suggesting it acts at a post-entry step of the replication cycle. Honokiol was also effective against more recent variants of SARS-CoV-2, including omicron and it inhibited other human coronaviruses as well. Our study suggests that honokiol is an interesting molecule to evaluate in animal studies and clinical trials to investigate its effect on virus replication and pathogenic (inflammatory) host responses.
Honokiol is a compound that shows both anti-inflammatory and antiviral effects, and therefore its effect on SARS-CoV-2 infection was assessed. This small molecule inhibited SARS-CoV-2 replication in various cell-based infection systems, with up to an ~1,000-fold reduction in virus titer.
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