A combinational approach to restore cytokine balance and to inhibit virus growth may promote patient recovery in severe COVID-19 cases

•Inhibition of IL-6 trans-signaling is crucial to rescue from cytokine storm.•sgp130Fc selectively inhibit IL-6 trans-signaling.•ADAM17/TACE prodomain inhibitor (TPD) effectively stop ADAM17 shedding activity.•Combination of sgp130Fc and TPD have potentiality to reduce cytokine storm in COVID-19.•Future trial may consider combination of sgp130Fc, TPD, anti-coagulant and antivirals for severe cases. The COVID-19 pandemic has led to twin public health and economic crises around the world. Not only has it cost hundreds of thousands of lives but also severely impacted livelihoods and placed enormous strain on community healthcare and welfare services. In this review, we explore the events associated with SARS-CoV-2 pathogenesis and host immunopathological reactivity due to the clinical manifestations of this coronavirus infection. We discuss that the metallopeptidase enzyme ADAM17, also known as tumor necrosis factor-α-converting enzyme, TACE, is responsible for shedding of angiotensin-converting enzyme 2 and membrane-bound interleukin (IL)-6 receptor. This leads to elevated pro-inflammatory responses that result in cytokine storm syndrome. We argue that cytokine balance may be restored by recovering an IL-6 trans-signaling neutralizing buffer system through the mediation of recombinant soluble glycoprotein 130 and recombinant ADAM17/TACE prodomain inhibitor. This cytokine restoration, possibly combined with inhibition of SARS-CoV-2 entry as well as replication and coagulopathy, could be introduced as a novel approach to treat patients with severe COVID-19. In cases of co-morbidity, therapies related to the management of associated disease conditions could ameliorate those clinical manifestations.