Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A Potential Drug Target in the Treatment of COVID-19

Novel coronaviruses (nCoVs) encode ion-channel proteins called viroporins such as protein E, open reading frame 3a (ORF3a) and ORF8a. These viroporins, via mechanisms such as lysosomal disruption and ion-redistribution in the intracellular environment, activate the innate immune signaling receptor NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasome. This leads to the production of inflammatory cytokines such as interleukin 1β (IL-1β), IL-6 and tumor necrosis factor (TNF), causing tissue inflammation during respiratory illness caused by CoV infection. Due to this crucial role in triggering inflammatory response to infection, the NLRP3 inflammasome appears to be a potential drug target in the treatment of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. This manuscript highlights the importance of NLRP3 inflammasome in the pathogenesis of nCoVs, discusses its known inhibitors and draws attention toward evaluation of these and similar known or novel agents for potential beneficial effects in the treatment of SARS-CoV-2 (COVID-19). The twenty-first century has witnessed the emergence of three novel coronaviruses (nCoVs): The first outbreak was caused by severe and acute respiratory syndrome coronavirus (SARS-CoV) that emerged in Southeast China in 2002, followed by the Middle East respiratory syndrome-related coronavirus (MERS-CoV) in 2012 (1). The recent pandemic which is caused by SARS-CoV-2 originated atWuhan city in China in late 2019, is causing a respiratory illness named as coronavirus disease 2019 (COVID-19) which is causing morbidity and mortality worldwide (2). CoVs carry a positive-sense, single-stranded RNA genome of about 30 kb and the virion nucleocapsid is surrounded by an envelop which is studded with spike (S), membrane (M), and envelop (E) proteins (3, 4). The spike (S) glycoprotein recognizes and interacts with its target called angiotensin converting enzyme 2 (ACE2) receptor on the host cell surface, mediating viral entry during the infection cycle (5). Identifying and exploiting promising therapeutic targets has always been an area of intensive research in the treatment of viral diseases. In this respect, the spike protein of SARS-CoV is also viewed as a drug target due to its role in a crucial checkpoint of viral infection, i.e., viral attachment and entry in to the host cell. Nevertheless, there are also other virus-host interactionmechanisms (see below) that offer attractive targets for potential therapies in the context of infections caused by SARS-CoVs.