Hydroxychloroquine: What Even is this Mysterious Drug?

Illustrated by Shelly Xu

Coronavirus reached the United States on Jan. 13, introducing the first large-scale respiratory epidemic since the Spanish Flu [13]. In the panic of the following months, hydroxychloroquine, a drug that most people had likely never heard of before, became prematurely touted as an effective treatment for coronavirus patients. When a short, uncontrolled French trial of 40 participants purportedly showed hydroxychloroquine treating COVID-19 patients, certain politicians heavily promoted its results [8,5]. The U.S. President Donald Trump even touted it to the American people as a “game changer,” and as “very powerful” [2]. The statements of these politicians influenced the public’s actions greatly: in certain parts of France, hydroxychloroquine prescriptions increased by 7,000% [9]. Unfortunately, later controlled studies showed no benefit of hydroxychloroquine, and the drug has since faded from the public eye and the hospital wards [3]. Despite hydroxychloroquine’s sudden publicity, some questions exist that are not often answered for the general public. What does hydroxychloroquine do and why did scientists even think it could treat COVID-19? 

There are a wide variety of pharmacological effects that hydroxychloroquine has on the body, some of which cause deleterious side effects like heart problems and some of which can be beneficial in certain infections. Many of hydroxychloroquine’s pharmacological effects come from its action in the lysosome, the acidic and hydrolytic compartment of the cell that breaks down waste and phagocytose pathogens. In a phenomenon called lysosomal trapping, high concentrations of hydroxychloroquine can get trapped inside of lysosomes. This phenomenon is due to the fact that uncharged hydroxychloroquine can enter the lysosome, but cannot exit the lysosome since it becomes positively charged in the lysosome’s acidic atmosphere [6]. By accumulating in the lysosome, the slightly basic hydroxychloroquine makes the lysosome less acidic, which inhibits the activation of lysosomal hydrolytic enzymes [10]. This inhibition confers some pharmacological benefits in treating malaria and certain viruses, but studies have not shown benefits in SARS-CoV-2. 

In the case of malaria, hydroxychloroquine enters the parasite lysosomes, prevents the crystallization of an ingested chemical group called heme, and causes the buildup of toxic heme groups that eventually kill the parasite [12]. In the case of viruses, hydroxychloroquine interferes with the deployment of the spike protein, a viral structure that allows for it to bind to the host membrane and fuse the host and viral membrane together, in turn allowing for viral genetic material to enter and infect the cell. These spike proteins activate in the lysosome when specific acid-activated proteases cleave spike protein precursors on the viral membrane [1]. Since hydroxychloroquine makes lysosomes less acidic, these proteases cannot be activated, and hence, the virus theoretically would not be able to use its spike proteins to infect the host cell. This kind of logic is what guided initial guesses of hydroxychloroquine working against COVID-19. 

Beyond getting trapped in the lysosome, hydroxychloroquine can also suppress excessive immune responses by inhibiting antigen presentation on professional antigen-presenting cells. It also inhibits the TLR9 innate immune receptor, which leads to suppressed inflammation; this is beneficial because inflammation causes many of the issues associated with autoimmune diseases [14,4]. For these two reasons, hydroxychloroquine is prescribed for patients with certain autoimmune diseases like rheumatoid arthritis or lupus. 

The pharmacology of hydroxychloroquine shows how a promising, multi-application drug that should work in theory must be thoroughly tested through scientific procedures in practice before being widely promoted. The consequences of our haste have caught up to us. The U.S. bought 29 million pills of hydroxychloroquine – money that could have been spent on PPE, funding research or providing economic relief [7]. People who actually needed hydroxychloroquine were also affected; in a survey done by the Lupus Research Alliance, over 31% of US lupus patients who needed hydroxychloroquine struggled to fill prescriptions from March to May [11]. Finally, the hydroxychloroquine may have caused side effects with lasting damage in an untold number of patients. The story of hydroxychloroquine is a sobering reminder that we cannot afford to handle scientific results in a reckless manner no matter how much we want them to be true. Influential figures must realize that public health is not a game – people die, livelihoods are shattered and everyone suffers. 

Edited by: Haleigh Pine
Illustrated by: Shelly Xu


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