Widely available lysosome targeting agents should be considered as potential therapy for COVID-19

•Lysosome targeting agents can disrupt endolysosomal maturation and inhibit viral replication•Lysosome targeting agents and lysosomotropic drugs should be explored as antiviral drugs for severe acute respiratory syndrome coronavirus-2•Some lysosomotropic drugs are commonly used pharmacological agents•Particular attention should be directed towards macrolides (e.g. azithromycin), non-steroidal anti-inflammatory drugs (e.g. indomethacin) and other lysosomotoropic agents While the coronavirus disease 2019 (COVID-19) pandemic advances, the scientific community continues to struggle in the search for treatments. Several improvements have been made, including discovery of the clinical efficacy of chloroquine (CQ) in patients with COVID-19, but effective treatment protocols remain elusive. In the search for novel treatment options, many scientists have used the in-silico approach to identify compounds that could interfere with the key molecules involved in entrance, replication or dissemination of severe acute respiratory syndrome coronavirus-2. However, most of the identified molecules are not available as pharmacological agents at present, and assessment of their safety and efficacy could take many months. This review took a different approach based on the proposed pharmacodynamic model of CQ in COVID-19. The main mechanism of action responsible for the favourable outcome of patients with COVID-19 treated with CQ seems to be related to a pH-modulation-mediated effect on endolysosomal trafficking, a characteristic of chemical compounds often called ‘lysosomotropic agents’ because of the physico-chemical properties that enable them to diffuse passively through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicles. This review discusses lysosomotropic and lysosome targeting drugs that are already in clinical use and are characterized by good safety profiles, low cost and wide availability. Some of these drugs –particularly azithromycin and other macrolides, indomethacin and some other non-steroidal anti-inflammatory drugs, proton pump inhibitors and fluoxetine – could provide additional therapeutic benefits in addition to the potential antiviral effect that is still to be confirmed by well-controlled clinical trials. As some of these drugs have probably been used empirically in the treatment of COVID-19, it is hoped that colleagues worldwide will publish patient data to enable evaluation of the potential efficacy of thes