Rational Drug Repurposing: Focus on Lysosomotropism, Targets in Disease Process, Drug Profile, and Pulmonary Tissue Accumulation in SARS-CoV-2 Infection/COVID-19

Abstract

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. Oxidative stress (e.g., enhanced ROS levels) has been demonstrated in animal models of SARS (Delgado-Roche and Mesta, 2020) and serves as a possible explanation why SARS-CoV-2 patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency develop intravascular hemolysis and methemoglobinemia (Palmer et al., 2020). Both, chloroquine and hydroxychloroquine, are supposed to trigger severe drug-induced hemolytic anemia in G6PD-deficient COVID-19 patients (Beauverd et al., 2020; Kuipers et al., 2020). Severe COVID-19 is associated with an atypical diffuse alveolar damage, ending in the acute respiratory distress syndrome (ARDS) (Huang et al., 2020), most likely accompanied by occurrence of syncytia as a result of a direct infection of cells by an infected neighboring cell without releasing a complete virus (Ou et al., 2020). Ceramides, in particular C₁₈-ceramide, are present in (sepsis-induced) cardiac dysfunction (Chung et al., 2017), and are effective in triggering exocytosis in rat PC12 cells (Tang et al., 2007); further they may contribute to SARS-CoV-2-related cell–cell fusion by exocytosis of viral S protein fractions and development of multinucleate syncytia. Non-structural protein nsp2 of SARS-CoV-2 was associated with host cell cell cycle progression, and apoptosis in host cells, suggesting an impact on disrupting the host cell environment (Yoshimoto, 2020) and apoptosis of endothelial cells (Varga et al., 2020). According to current knowledge, cleavage-mediated fusion of viral S protein with host cells can occur either immediately at the cell surface by TMPRSS2 or within the lysosome catalyzed by lysosomal cathepsin L (Belouzard et al., 2012). The lysosomal cathepsin L induced fusion of SARS particles bound to ACE2 with host cells (Millet and Whittaker, 2015) is sensitive to lysosomal pH. Hence both, TMPRSS2 and cathepsin L, display promising targets of prophylaxis and treatment of SARS-CoV-2 infection/COVID-19. In severe COVID-19, SARS-CoV-2 is likely to cause both, pulmonary and systemic inflammation, thus leading to multi-organ dysfunction in high risk populations. Significantly higher concentrations of IL-8, TNFα, and IL-6 in deceased patients (Chen et al., 2020) are suggesting a rapid and severe deterioration during SARS-CoV-2 infection associated with CRS/cytokine storm syndrome (Mehta et al., 2020). Lysosomotropism is a biological characteristic of small molecules and always present in addition to intrinsic pharmacological effects. Various well-known approved drugs such as amitriptyline, chlorpromazine, sertraline, and imipramine share lysosomotropic characteristics (Figure 1A) (Kornhuber et al., 2008; Blaess et al., 2018). Regardless of their pharmacological effects, they are accumulating in lysosomes raising the lysosomal pH from 4.5–5 to 6–6.5, beyond the optimum of most of the lysosomal enzymes, including cathepsin L. Since no effects of lysosomotropic aminoglycoside antibiotics on free cathepsin L (Zhou et al., 2016) or other lysosomotropic drugs on lysosomal enzymes such as acid sphingomyelinase exist (Blaess et al., 2018), a selective inhibition is unlikely. FIGURE 1. (A) Variety of approved lysosomotropic compounds for various indications (Kornhuber et al., 2008; Blaess et al., 2018). Achievement of the desired lysosomotropic effect depends on the active compound, the dosage, and accumulation in lysosomes. Unless indicated, maximum daily doses are split into three applications. *Lysosomotropism very likely, but not yet confirmed, lysosomal drug concentration (effect) within the therapeutic margin expected; dosage: ^#single dose per day; ^xin vitro anti-SARS‐CoV tested, ^xxin vitro anti-SARS-CoV and anti-SARS-CoV-2 tested (Vincent et al., 2005; Kornhuber et al., 2008; Dyall et al., 2014; Zhou et al., 2016; Blaess et al., 2018; Liu et al., 2020; Weston et al., 2020). (B) Cellular targets, cellular effects, and effects related effects of lysosomotropic active compounds in SARS-CoV-2 infection/COVID-19 (Vincent et al., 2005; Masters, 2006; Mingo et al., 2015; Zhou et al., 2016; Blaess et al., 2018; Varga et al., 2020; Zhou et al., 2020). Lysosomotropic compounds target in mammalian cells three major targets related to SARS-CoV-2 infection/COVID-19: cathepsin L (1), gene expression of inflammation-relevant genes (2), C₁₆-ceramide and C₁₈-ceramide synthesis, and apoptosis of host cells (3). Addressing targets 1–3 results in...