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 SARSCoV and MERS-CoV, which can lead to fatal infections with around 10% and 39% mortality, respectively. 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-?B 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.
Even though cell viability is not impaired by the applied LASAG concentrations, the anti-coronaviral action of LASAG in cell culture lies in a millimolar range, likewise to the anti-viral action of ASA against IV [38]. To achieve a 20 mM LASAG concentration in the blood, 6.53 g/L would be needed, which is toxic [75]. The Cmax in the blood after applying 500 mg ASA i.v. is 54.25 mg/L and 4.84 mg/L after oral application [76]. Nevertheless, treatment of patients with a CoVcaused severe acute respiratory syndrome via inhalation might allow achieving locally effective LASAG concentrations. Results from a clinical study investigating the effectiveness of inhaled lysineacetylsalicylate in the treatment of asthma showed, that patients that received a dosage of 720 mg of inhaled LASAG twice a day over a twoweek period did not experience any significant side effects [77]. Also, a dose escalation study of inhaled LASAG in humans for the clinical development of an antiviral treatment of IV infections demonstrated that inhalative doses up to 750 mg LASAG were safe and well tolerated without serious adverse events.
Furthermore, administration of aerosolic ASA via intubation directly into the trachea resulted in increased survival rates of mice infected with a lethal dose of IV [38]. In light of the fact that currently no approved anti-viral treatment against severe CoV-infections exist, it should be mentioned that LASAG (i) is widely available and it is tested and approved for humans, (ii) it targets cellular functions, (iii) is so far not known to target CoV functions, which reduces the chance that resistant virus variants emerge and (iv) adjacent to its direct anti-viral property, patients could also benefit from the effects of LASAG on infection-related symptoms based on the analgetic- and anti-inflammatory characteristics of LASAG. In conclusion, we were able to demonstrate that LASAG inhibits virus-induced NF-?B activity, which might be connected to the antiviral effect against CoV, including the impaired formation of RTCs and/or DMVs in CoV-infected cells, leading to reduced viral RNA production and consequently decreased production of viral proteins, resulting in an overall diminished virus titre. Acknowledgments We want to thank C. Drosten, Bonn, Germany, for providing MERS-CoV EMC/2012. This work was funded in part by the German Centre for Infection Research (DZIF), partner site Giessen, Germany (TTU Emerging Infections to S.P. and J.Z.), and the DFG-funded Collaborative Research Centre 1021 "RNA viruses: RNA metabolism, host response and pathogenesis" (SFB1021; projects A01 and C01 to J.Z. and S.P., respectively). Furthermore the work was supported in part by a fund of the Activaero GmbH (acquired by Vectura).
In summary, the early use of aspirin in covid-19 patients, which has the effects of inhibiting virus replication, anti-platelet aggregation, anti-inflammatory and anti-lung injury, is expected to reduce the incidence of severe and critical patients, shorten the length of hospital duration and reduce the incidence of cardiovascular complications.