*3.1.4 Drug repurposing targeting immune response modulators to treat SARS-CoV-2*

Clinical symptoms resulting from SARS-CoV-2 infection are heterogeneous. Recent reports have shown that the cytokine storm effect may play a significant

#### **Figure 1.**

*Boceprevir (green), a HCV NS3/4A protease inhibitor, bound to SARS-CoV-2 3C-like protease (gray surface representation) with several key drug-protein interactions shown. Hydrogen bonds are shown as yellow dotted lines. PDB accession code: 6zru.*

role in disease progression, potentially leading to multiple organ failure and death [119]. Immune response-related proteins have been proposed as potential targets for treatment options [120, 121]. Even though effectively suppressing cytokine storm does not directly combat the viral infection itself, it can be a crucial treatment option against COVID-19. It has previously been demonstrated that melatonin has beneficial effects on infection induced models of respiratory disease and associated complications [122]. Recently evidence also surfaced that it can inhibit COVID-19 induced cytokine storm [123]. Tocilizumab, an interleukin antagonist used for rheumatoid arthritis, is an immunosuppressor and was thus posited to be effective at reducing inflammation caused by SARS-CoV-2 [124]. It has recently become one of the first drugs to be recommended by the WHO as an effective treatment against COVID-19 [125]. Even though this is very promising there is an issue with the availability and affordability of this drug [126].

Researchers at Johns Hopkins found that the drug prazosin, an alpha-1 blocker used to treat high blood pressure, can prevent cytokine storms and that it significantly strengthened survival following inflammatory stimuli in preclinical models. This study is now in clinical trials [127].

#### *3.1.5 Drug repurposing targeting pyroptosis*

Sepsis is a systemic inflammatory response syndrome reulsting from dysregulation of host immunity. It is one of the deadliest clinical symptoms of severe SARS-CoV-2-infected patients [128]. Sepsis treatment normally mainly relies on the administration of intravenous antibiotics. However, since SARS-CoV-2 viral sepsis is not bacterial in nature the efficacy is low. Treatment is difficult, typically consisting of supplying oxygen and assisted breathing using a ventilator. Cocktails of antivirals and immune suppressors are also given but usually only have limited effect [129]. Approximately one-third of the discharged patients will die and one-sixth will suffer severe persistent impairments in the following year [130]. These facts taken together demonstrate the urgency and significance to find new treatments.

Sepsis is associated with pyroptosis (inflammatory programmed cell death) that is triggered by proinflammatory signals [131]. When viruses invade the host cell, inflammasomes are activated which in turn triggers an inflammatory response [132]. Pore-forming protein gasdermin D (GSDMD) is cleaved by activated Caspase-1, releasing its N-terminal domain [133]. The GSDMD N-terminal domain

#### *Drug Repurposing Techniques in Viral Diseases DOI: http://dx.doi.org/10.5772/intechopen.101443*

induces the formation of a large plasma membrane pore, resulting in pyroptosis [134]. Under normal circumstances pyropthosis can be good response, being able to trigger cell death of infected cells, releasing the pathogens and stimulating subsequent phagocytosis, protecting against infections [135]. However, excessive activation of pyroptosis will exacerbate sepsis or excessive cell death, causing immunity dysregulation [136, 137].

Disulfiram is approved for the treatment of chronic alcoholism. In a study conducted by Boston Children's Hospital, researchers found that disulfiram posesses inhibiting potential towards GSDMD both in *in vitro* cell assays and in *in vivo* mouse experiments. The experiment results showed that disulfiram inhibit the formation of the GSDMD pore by covalently modifying Cys191 of human GSDMD [138]. These results indicate that disulfiram could potentially be used to combat the pyroptotic effects induced by sars-cov-2 infection, hopefully reducing the negative clinical outcomes.
