D, L-lysine acetylsalicylate + glycine Impairs Coronavirus Replication

Abstract

Coronaviruses (CoV) belong to the large family Coronaviridae within the order of Nidovirales. Among them, several human pathogenic strains (HCoV) are known to mainly cause respiratory diseases. While most strains contribute to common cold-like illnesses others lead to severe infections. Most prominent representatives are SARS-CoV and MERS-CoV, which can lead to fatal infections with around 10% and 39% mortality, respectively. This resulted in 8098 casualties in the 2002/2003 SARS-CoV outbreak and in 1806 documented human infections (September 2016) during the recent ongoing MERS-CoV outbreak in Saudi Arabia. Currently patients receive treatment focusing on the symptoms connected to the disease rather than addressing the virus as the cause. Therefore, additional treatment options are urgently needed which would ideally be widely available and show a broad affectivity against different human CoVs. Here we show that D, L-lysine acetylsalicylate + glycine sold as "Asprin i.v. 500mg®" (LASAG), which is an approved drug inter alia in the treatment of acute pain, migraine and fever, impairs propagation of different CoV including the highly-pathogenic MERS-CoV in vitro. We demonstrate that the LASAG-dependent impact on virus-induced NF-κB activity coincides with (i) reduced viral titres, (ii) decreased viral protein accumulation and viral RNA synthesis and (iii) impaired formation of viral replication transcription complexes.

Inhibition of Cytosolic Phospholipase A2α Impairs an Early Step of Coronavirus Replication in Cell Culture

“…As shown by the results in Fig. 2D and a previous study (42), we failed to obtain evidence for anticoronaviral activities of LOX and COX1/2 inhibitors, arguing against a major role of AA (and its downstream metabolites) in coronavirus replication. We therefore considered it more likely that the other product of PLA 2 ␣ activity (i.e., the LPL) has a role in supporting viral replication, for example, by providing specific lipid components required to form viral ROs.…”

“…None of these inhibitors was found to have an effect on coronavirus replication ( Fig. 2A) (42), contradicting the idea of a major role of AA-dependent pathways involving COX1/2 and LOX and their products in coronavirus replication, at least in vitro. Consistent with this hypothesis, the addition of AA to the cell culture medium failed to restore coronavirus replication in Py-2-treated cells (unpublished data).…”

“…2C), but not for inhibitors of enzymes acting downstream from cPLA 2 ␣ in arachidonic acid (AA)-dependent pathways, such as cyclooxygenases 1 and 2 (COX1/2) and lipoxygenase (LOX) ( Fig. 2D) (42), which metabolize AA to produce important inflammation mediators. Taken together, the data support a critical role of (activated) cPLA 2 ␣ in HCoV-229E replication, suggesting that this lipolytic enzyme has a more general role in ϩRNA virus replication than previously thought.…”

Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses

“…5). In the presence of 10 nM silvestrol, we observed a significant decrease of both viral double-stranded RNA (dsRNA) and the HCoV-229E nsp8 protein, which were used as markers for viral genome expression and RTC formation (Lundin et al, 2014;Müller et al, 2016). At 100 nM silvestrol, nearly no viral dsRNA and nsp8 could be detected (Fig.…”

“…Immunofluorescence was performed as described previously (Müller et al, 2016). Briefly, MRC-5 cells were infected with HCoV-229E (MOI of 3) and treated with the indicated concentrations of silvestrol for 12 h p.i.…”