Chloroquine to fight COVID-19: A consideration of mechanisms and adverse effects?

The COVID-19 outbreak emerged in December 2019 and has rapidly become a global pandemic. A great deal of effort has been made to find effective drugs against this disease. Chloroquine (CQ) and hydroxychloroquine (HCQ) were widely adopted in treating COVID-19, but the results were contradictive. CQ/HCQ have been used to prevent and treat malaria and are efficacious anti-inflammatory agents in rheumatoid arthritis and systemic lupus erythematosus. These drugs have potential broad-spectrum antiviral properties, but the underlying mechanisms are speculative. In this review, we re-evaluated the treatment outcomes and current hypothesis for the working mechanisms of CQ/HCQ as COVID-19 therapy with a special focus on disruption of Ca²⁺ signaling. In so doing, we attempt to show how the different hypotheses for CQ/HCQ action on coronavirus may interact and reinforce each other. The potential toxicity is also noted due to its action on Ca²⁺ and hyperpolarization-activated cyclic nucleotide-gated channels in cardiac myocytes and neuronal cells. We propose that intracellular calcium homeostasis is an alternative mechanism for CQ/HCQ pharmacology, which should be considered when evaluating the risks and benefits of therapy in these patients and other perspective applications.