NB 06: From a simple lysosomotropic aSMase inhibitor to tools for elucidating the role of lysosomes in signaling apoptosis and LPS-induced inflammation

COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks

“…In ACE2 and TMPRSS2 expressing lung epithelium-derived cells (Calu-3 and H3255) nafamostat was extremely efficient (EC 50 about 10 nM), whereas in non-TMPRSS2-expressing cells (293T and VeroE6) nafamostat was demonstrated to be hardly effective (EC 50 about 30 µM) [ 50 , 119 ]. In this context, an EC 50 within the range of 5–50 µM usually indicates an inhibitory effect grounded in lysosomotropism [ 36 , 44 , 53 ]; a hypothesis which is supported by the chemical structure and chemical characteristics of nafamostat.…”

“…A similarly pronounced dependence on certain enzymes, proteins, cell lines, and in particular on the time of application during the disease process, is assumed to be unlikely for lysosomotropic active compounds. The EC 50 of active compounds is typically within 5–30 µM [ 36 , 41 ].…”

“…Apoptosis in mammalian cells is characterized by an increase in C 16 -ceramide [ 36 , 37 ]. Both can be blocked via lysosomotropic compounds such as NB 06, chlorpromazine, and imipramine [ 36 ]; apoptosis via chloroquine [ 38 , 39 ] and with its lysosomotropic characteristics C 18 -ceramide most likely as well.…”

“…Apoptosis in mammalian cells is characterized by an increase in C 16 -ceramide [ 36 , 37 ]. Both can be blocked via lysosomotropic compounds such as NB 06, chlorpromazine, and imipramine [ 36 ]; apoptosis via chloroquine [ 38 , 39 ] and with its lysosomotropic characteristics C 18 -ceramide most likely as well. The lysosomotropic compound NB 06 down-regulates the expression of pro-inflammatory cytokines (e.g., IL-1B, IL-6 and IL-23A in LPS-stimulated macrophages [ 36 ] and desipramine protects against sepsis-induced cardiac dysfunction in a murine sepsis model [ 40 ].…”

“…Lysosomotropism is a commonly occurring and often neglected biological characteristic of small molecules leading to accumulation in lysosomes, which is present in addition to their intrinsic receptor-mediated or enzymatic pharmacological effects. Regardless of the medical indications for which they have been used, many (active) compounds possess lysosomotropic characteristics [ 36 , 41 , 42 , 43 , 44 , 45 , 46 ]. Therefore, they are potential active compounds for the treatment of SARS-CoV-2 viral infection of airway epithelial cells (type II pneumocytes), such as chloroquine in Sindbis virus infection [ 44 ].…”