By Xiping Zhan, Ph.D.

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. Two structurally related quinoline drugs, chloroquine (CQ) and hydroxychloroquine (HCQ), were widely adopted in treating COVID-19, but the results were contradictory. 

As a generic drug, quinine was initially employed to treat malaria but has since been succeeded by CQ and its derivative, HCQ. These anti-inflammatory drugs then were used as treatments for rheumatoid arthritis and systemic lupus erythematosus.

More recently, CQ/HCQ treated several viral infections, such as hepatitis A and AIDS, leading to their investigation as a treatment for the severe acute respiratory syndrome (SARS) outbreak in 2003. 

Still, while CQ/HCQ has potential broad-spectrum antiviral properties, the underlying mechanisms are speculative. In our review of published research in the journal Heliyon, we re-evaluate the treatment outcomes and current hypotheses for how CQ/HCQ may be effective as COVID-19 therapy.

The first proposed mechanism of CQ/HCQ is through their ability to elevate pH (lowering acidity), which blocks the fusion of the viral spike proteins with the host cell. 

Next, based on the use of CQ/HCQ with rheumatoid arthritis and lupus that reduces inflammation, CQ/HCQ may play a role in COVID-19 by suppressing fatal hyperinflammation, also known as the “cytokine storm,” an overabundance of the body’s innate immune response. Although suppression of the cytokine storm is beneficial in severe COVID-19 cases, this may also disrupt subsequent immune responses to viral infections.

The third mechanism we focused on was the disruption of calcium ion (Ca2+) signaling. CQ/HCQ may block virulence by interfering with the calcium ion signaling required for viral life cycles in vulnerable cells, such as airway epithelial cells and pulmonary capillary endothelial cells. Several studies show evidence that this and other various means of calcium ion modulation may be how CQ/HCQ serves as a broad-spectrum antiviral agent. 

The potential toxicity of CQ/HCQ is also noted, with their adverse effect on different types of cells (cardiac, neuronal) rendering it a tricky drug to employ for clinical applications. For example, evidence shows that CQ/HCQ heart toxicity derives from disrupted electrical conduction. There are also other side effects of CQ/HCQ including retinopathy, ototoxicity, itching, and mood disturbance, so the close monitoring of neurological, visual, and auditory symptoms is also warranted.

Further research is needed to assess whether modulating the disruption of calcium ion signaling can be a target for CQ/HCQ to suppress COVID-19 and other viral infections.

A 2015 Emerging Research Grants scientist, Xiping Zhan, Ph.D., was generously funded by the Les Paul Foundation. He is a research assistant professor of physiology and biophysics at Howard University College of Medicine, Washington, D.C. His paper about quinine’s effect on hearing loss and tinnitus appeared in the Winter 2019 issue of Hearing Health magazine.