Can an Old Ally Defeat a New Enemy?

July 28, 2020 315 Paul A. Gurbel , MD Kevin P. Bliden, MBA Karsten Schrör, MD I nfection with the beta coronavirus severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) is a worldwide public health nightmare with nearly 5 million confirmed cases and >300 000 deaths. The fact that it has no proven therapy has created an urgency to find safe and effective early treatments. We must open our eyes to all reasonable candidates. Acetylsalicylic acid (ASA), the wonder drug of the last century, may be a magic bullet to repulse our new enemy. In the war against cardiovascular disease, the efficacy of ASA for secondary prevention is established and results largely from the acetylationinduced inhibition of platelet cyclooxygenase-1, a key mediator of thrombosis.1 In the war against viral disease, another important effect of ASA, mediated by the salicylate component, should be exploited. ASA inhibits a key nuclear transcription factor, nuclear factor-κB (NF-κB).1 Viral replication and the ensuing inflammatory response (cytokine storm) mandate activation of NF-κB in the host cell. The invading viruses conduct their “hostile takeover” of the cell by inactivating IκB, the endogenous inhibitor of NF-κB.2 Viruses do this by activating a kinase, IκB kinase, which phosphorylates IκB (Figure). ASA and salicylate are known inhibitors of IκB kinase at millimolar concentrations. This effect is not seen with indomethacin or other nonsteroidal anti-inflammatory drugs, is concentration-dependent, and is reportedly mediated by blocking ATP binding to IκB kinase.1 In in vitro studies, D, L-lysine acetylsalicylate+glycine (LASAG) inhibited low (HCoV-229E) and highly (Middle East respiratory syndrome coronavirus) pathogenic beta coronavirus strain replication.2 Cytotoxic concentrations were >20 mmol/L, whereas the EC50 values for vital titers were 1.31 mmol/L for HCoV-229E and 3.91 mmol/L for Middle East respiratory syndrome coronavirus, suggesting a potential therapeutic window. LASAG also inhibited virus-induced NF-κB activity and decreased viral protein formation, RNA synthesis, and the formation of replication transcription complexes.2 In human lung epithelial cells infected with influenza A, 5 mmol/L LASAG inhibited IκB kinase–mediated NF-κB activation and virus production. In the same report, inhaled LASAG was associated with a survival benefit in mice infected with a severe influenza strain. Finally, in 24 patients afflicted with severe influenza, nebulized LASAG 3 times a day to achieve an estimated total daily alveolar dose of 133.5 mg was associated with faster alleviation of symptoms compared with control subjects.3 Systemic concentrations of ASA and salicylate obtained by oral conventional ASA may not reach the airway and alveolus at a level for meaningful antiviral effects. Moreover, high oral ASA doses can be limited by salicylate toxicity caused by (reversible) uncoupling of oxidative phosphorylation at anti-inflammatory doses and effects of cyclooxygenase inhibition.1 However, treatment of patients by inhalation would likely achieve locally effective concentrations without major toxicity. Repeated administration of aspirin is followed by accumulation of salicylate resulting from prolongation © 2020 American Heart Association, Inc.