R-Propranolol Has Broad-Spectrum Anti-Coronavirus Activity and Suppresses Factors Involved in Pathogenic Angiogenesis

Abstract

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.

Epi-Cyclophellitol Cyclosulfate, a Mechanism-Based Endoplasmic Reticulum α-Glucosidase II Inhibitor, Blocks Replication of SARS-CoV-2 and Other Coronaviruses

“…We next evaluated the efficacy of 1,6- epi -cyclophellitol cyclosulfate 11 , in comparison to our most potent iminosugar, naphthyl-deoxynojirimycin 2 , as well as Miglustat 1 in a more advanced model of primary human bronchial epithelial cells that were cultured at the air–liquid interface (ALI-PBEC), as we described previously. , Thus, ALI-PBEC cells were infected with SARS-CoV-2 (10 5 PFU per insert; estimated MOI ∼0.1) and treated with compounds on the apical side of the cells for 2 h. For uninfected controls, PBS was used instead of virus. The compounds were also present in the basal medium during the whole experiment until 48 hpi, when samples were harvested.…”

“…RNA was isolated by magnetic bead isolation, as described in ref . Equine arteritis virus (EAV) in AVL lysis buffer (Qiagen) was spiked into the isolation reagent as an internal control for extracellular RNA samples.…”

Antivirals and Vaccines

“…The effect of oral pamapimod with pioglitazone on COVID-19 development and recovery in non-hospitalised patients infected with SARS-CoV-2 is currently being investigated in a Phase II clinical trial (KIN-FAST trial, NCT05659459). On the other hand, Thaler et al [ 6 ] show that R-propranolol exhibits broad-spectrum anti-coronavirus activity, inhibiting the replication of MERS-CoV, SARS-CoV and SARS-CoV-2 in several cell lines and in human primary bronchial epithelial cells. Using time-of-addition assays, the authors show that R-propranolol inhibits an unidentified post-entry step of the SARS-CoV-2 replication cycle, likely via a host cell factor.…”

“…SARS-CoV-2 infection leads to pathogenic blood vessel formation in the lungs (intussusceptive angiogenesis), which is associated with the upregulation of pro-angiogenic factors such as ANGPTL4 and VEGFA [ 8 ]. Thaler et al [ 6 ] also investigated the effect of propranolol on ANGPTL4 expression. They found that SARS-CoV-2 upregulated ANGPTL4 in endothelial and other cells, which was suppressed by R-propranolol in a process that was partially independent of the antiviral effect.…”