Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) have been proposed as treatments for COVID-19. These drugs have been studied for many decades, primarily in the context of their use as antimalarials, where they induce oxidative stress-killing of the malarial parasite. Less appreciated, however, is evidence showing that CQ/HCQ causes systemic oxidative stress. In vitro and observational data suggest that CQ/HCQ can be repurposed as potential antiviral medications. This review focuses on the potential health concerns of CQ/HCQ induced by oxidative stress, particularly in the hyperinflammatory stage of COVID-19 disease. The pathophysiological role of oxidative stress in acute respiratory distress syndrome (ARDS) has been well-documented. Additional oxidative stress caused by CQ/HCQ during ARDS could be problematic. In vitro data showing that CQ forms a complex with free-heme that promotes lipid peroxidation of phospholipid bilayers are also relevant to COVID-19. Free-heme induced oxidative stress is implicated as a systemic activator of coagulation, which is increasingly recognized as a contributor to COVID-19 morbidity. This review will also provide a brief overview of CQ/HCQ pharmacology with an emphasis on how these drugs alter proton fluxes in subcellular organelles. CQ/HCQ-induced alterations in proton fluxes influence the type and chemical reactivity of reactive oxygen species (ROS).
Highlights
At the writing of this review, there was no Food and Drug Administration (FDA)approved drugs for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA virus infection, which causes the coronavirus disease 2019 (COVID-19)
In vitro data showing that CQ forms a complex with free-heme that promotes lipid peroxidation of phospholipid bilayers are relevant to COVID-19
Free-heme induced oxidative stress is implicated as a systemic activator of coagulation, which is increasingly recognized as a contributor to COVID-19 morbidity
Summary
At the writing of this review (mid-2020), there was no Food and Drug Administration (FDA). The ability of these weakly basic and lipophilic compounds: (1) to bind biological membranes; (2) to accumulate the lumens of acidic subcellularand vesicles and alterStructure/Function proton fluxes; (3) to induce generalized The ability of these weakly basic and lipophilic compounds: (1) to bind biological membranes; (2) to CQ and HCQ both belong to a class of compounds (see Figures 1 and 2) termed cationic accumulate in the lumens of acidic subcellular vesicles and alter proton fluxes; (3) to induce amphiphilic drugs or CADs [30]. The notion that CQ/HCQ could alkalinize endosomal-lysosomal pH and thereby inhibit the replication of viruses requiring an acidic pH has been an attractive hypothesis [60] This potential mechanism is often proposed as a rationale for the CQ/HCQ treatment of COVID-19 [61]. As indicated in Figure theO mitochondrial respiratory chain electron transport chain (ETC) is a thanofthe carrier in the ETC, as metabolism, shown in reaction
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