Immunosuppressants
Three clinical trials are recruiting COVID-19 patients to test the efficacy of the immunosuppressant sirolimus(NCT04341675, NCT04371640 and NCT04374903), whereas no clinical study on the calcineurin inhibitor cyclosporine in COVID-19 has been recorded, despite it has been hypothesized as potential candidate for SARS-CoV-2 infection (Cure, Kucuk & Cumhur Cure, 2020). Both the immunosuppressants can interfere with NLRP3 inflammasome. Sirolimus inhibits NLRP3 inflammasome activation in macrophages through autophagy induction (Ko, Yoon, Lee & Oh, 2017), whereas cyclosporine targets cyclophilin D to avoid the opening of mitochondria permeability transition pore (MPT), which is strictly involved in NLRP3 inflammasome activation (Iyer et al., 2013).
Another well-known NLRP3 inhibitor included in several clinical protocols for COVID-19 patients is the classical anti-mitotic drug colchicine, with at least ten ongoing clinical trials (NCT04328480, NCT04322682, 2020-001841-38, NCT04392141, 2020-001511-25, NCT04322565, NCT04375202, NCT04360980, 2020-001603-16, NCT04363437) and 3 others ready to start (NCT04367168, NCT04355143, NCT04326790). Several mechanisms have been proposed to explain how colchicine can suppress NLRP3 inflammasome activation. First, colchicine can inhibit the expression of pyrin gene, avoiding the assembly of the NLRP3 inflammasome complex (Nidorf, Eikelboom & Thompson, 2014). Second, colchicine inhibits activation of caspase-1 and mature IL-1β (Otani et al., 2016). Third, colchicine inhibits P2X7-induced pore formation, a key step in NLRP3 inflammasome activation following ATP exposure (Marques-da-Silva, Chaves, Castro, Coutinho-Silva & Guimaraes, 2011).
Other interesting small molecules with immunomodulatory properties, already proposed for COVID-19 infection and with documented modulatory activity on NLRP3 inflammasome, are the Janus kinase (JAK) inhibitor baricitinib and the Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib. A study on baricitinib has already been concluded with interesting results (NCT04358614) and others are recruiting patients for both the treatments (Baricitinib: NCT04320277 and NCT04390464; Acalabrutinib: NCT04346199 and NCT04380688). Experimental evidence for key roles of the JAK and BTK cascades in either activation of the NLRP3 inflammasome and diabesity pathogenesis have been reported in the literature (Collotta et al., 2020; Furuya et al., 2018)
Up to nowadays six clinical trials (NCT04347980, NCT04325061, NCT04395105, NCT04344730, NCT04360876, NCT04327401), reported on clinicaltrials.gov are recruiting patients to test the efficacy of the corticosteroid dexamethasone , whose beneficial effects in airway inflammation has been recently demonstrated to involve lung inhibition of the activity of NLRP3 inflammasome and the release of IL-1β and IL-18 (Guan, Ma, Fan, Chen, Miao & Wu, 2020).