Rational Drug Repurposing: Focus on Lysosomotropism, Targets in Disease Process, Drug Profile, and Pulmonary Tissue Accumulation in SARS-CoV-2 Infection/COVID-19
The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the disease-causing pathogen of Coronavirus disease 2019 (COVID-19). (Pre)clinical research to identify rapidly available small molecules for the treatment of SARS-CoV-2 infections/COVID-19 has focused to date on the approved lysosomotropic antimalarials chloroquine and hydroxychloroquine, the investigational remdesivir (GS-5734, compassionate use), and the anti-inflammatory corticosteroid dexamethasone (COVID-19 Treatment Guidelines Panel, 2020). Lopinavir/ritonavir and other HIV protease inhibitors, however, were discontinued as treatment options in COVID-19 demonstrating no clinical benefit in clinical trials. Despite encouraging results in treating hospitalized patients with COVID-19 requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) with remdesivir and dexamethasone, there is still a lack of active compounds exhibiting pan-coronavirus antiviral activity, tackling or preventing host cell infection, forming syncytia, endotheliitis, or the cytokine release syndrome (CRS)/cytokine storm syndrome in COVID-19. Target-oriented and in particular site of action-oriented drug repurposing of small molecules has the potential to close the gap in prophylaxis and treatment of mild and moderate COVID-19 and to reduce mortality in severe cases.