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Abstract
Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the disease-causing pathogen of the pandemic Coronavirus disease 2019 (COVID-19)outbreak, posing serious challenges to health care systems worldwide
Dexamethasone and the recently approved nucleotide prodrug remdesivir are recommended for hospitalized COVID-19 patients requiring supplemental oxygen or noninvasive ventilation, and dexamethasone in case of extracorporeal membrane oxygenation (ECMO) or invasive mechanical ventilation
Repurposing of approved active compounds, with particular regard to their metabolites accumulating in the lysosomes of pulmonary tissue and mononuclear cells, could be a strategy to bridge this gap and to achieve a better outcome, unlike chloroquine administration in COVID-19 [1] and SARS [7]
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the disease-causing pathogen of the pandemic Coronavirus disease 2019 (COVID-19). Efficacy on targets cathepsin L, TMPRSS2, formation of syncytia, SARS-CoV-2 RdRp, lysosomal C16 -/C18 -ceramide synthesis, endothelial stress in systemic inflammation, and CRS/cytokine storm [8,10,11,12,22,25,26,27,28,29]: (+◦ ) proven in vitro; (+) is very likely; (O) is (mediated) possible; (-) no effect. Lysosomotropic compounds are supposed to tackle the CRS/cytokine storm syndrome in transition to COVID-19 They prevent the required lysosomal acidification for fusion-activating cathepsin L activity to diminish or prevent airwave cell infection by releasing viral RNA. In presence of lysosomotropic compounds, the ongoing synthesis of long-chain ceramides leads to an accumulation of long-chain ceramides (e.g., C24:1 -ceramide) [22] without triggering vesicle formation [30]
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