Small molecules targeting endolysosomal acidification and signaling in sepsis and severe SARS-CoV-2 infection/COVID-19

Sepsis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, its form disease 2019 (COVID-19), represent the major medical challenges of modern era. Therapeutic options are limited, mostly symptomatic, partially relying on antibodies corticosteroids and, in case SARS-CoV-2 supplemented by antiviral drug remdesivir, more recently molnupiravir, nirmatrelvir/ritonavir, Janus kinase (JAK) inhibitors tofacitinib baricitinib. infection/COVID-19 share many features at level pathophysiology pro-inflammatory mediators, thus enabling a common management strategy. New ideas successfully targeting prognostic severity mortality marker pentraxin 3 (PTX3) sepsis infection/COVID-19; complement (C3/C3a/C3aR C5/C5a/C5aR axis); tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 expression; IL-6-triggered expression C5aR receptor vascular endothelial cells; release anti-inflammatory IL-10 still missing. Small molecules with lysosomotropic characteristics such as approved drugs amitriptyline, desloratadine, fluvoxamine, azelastine, ambroxol have demonstrated their clinical benefits rodent models or trials COVID-19; however, exact mode action remains to be fully elucidated. Addressing disease-relevant targets viral infection host cells, shedding toll-like receptors (TLRs), mediators TNF-α, IL-1β, IL-6, PTX3, C5aR, highlight advantages this multi-target approach comparison current standards. Rational repurposing screening for active compounds virtually exclusively pharmacologic effects is opportunity improve prophylaxis treatment and/or COVID-19.