Since we last published our blog Deciphering the Biology of the 2019 Coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen has made its way around the world, with many countries closing down completely to help manage the spread of the virus. The rapid spread of the disease has pushed virologists and clinicians to collaborate in order to develop new therapies faster than ever before. To expediate the development and approval process, many are looking at repurposing drugs for COVID-19.
Chloroquine and Hydroxychloroquine
Chloroquine, which has been around since the 1930s, and its less toxic alternative, hydroxychloroquine, have been used previously as drugs to treat patients with malaria, due to its ability to bind heme inside parasitic cells and cause cell lysis.1 It has also been used as an anti-neoplastic agent due to its ability to inhibit autophagy. Autophagy is commonly dysregulated in many types of cancer, by preventing fusion of the autophagosome with the lysosome.2
In 2005, a group that included scientists from the Centers for Disease Control and Prevention (CDC) and the Clinical Research Institute of Montreal (located right next to us in Quebec) published a paper that described the efficacy of chloroquine in stopping infection with the first iteration of the SARS coronavirus. They tested the drug in primate cell cultures, showing that chloroquine increased endosomal pH and tinkered with the glycosylation of angiotensin-converting enzyme 2 (ACE2), the host receptor necessary for SARS membrane docking.3
Looking back, that 2005 paper is ground-breaking as chloroquine is now considered by the World Health Organization (WHO) as one of the top four potential therapies to fight SARS-CoV-2. The WHO is currently launching a megatrial with several promising therapeutic agents, including both chloroquine and hydroxychloroquine. Though a few groups have reported beneficial effects using either drug, there is skepticism as to whether the dosage required might be too toxic in humans.4
One of the first pre-existing compounds to be considered for treating COVID-19 is the nucleoside analog, remdesivir. Remdesivir was previously developed and tested by Gilead Sciences as a treatment for Ebola, another single-strand RNA virus, during the 2014 Ebola outbreak; however, clinical trials were mostly unsuccessful. Instead, scientists decided to test its efficacy in cell and animal models of SARS and Middle East Respiratory Syndrome (MERS), showing that it has the potential to work in humans.5
Remdesivir is a phosphoramidate prodrug of an adenine analogue, which acts primarily as a reverse transcriptase inhibitor. The virus is tricked into incorporating remdesivir into viral RNA, which prematurely terminates transcription of the strand.6,7 This drug is also included in the WHO’s list of top COVID-19 therapeutics, and there is already some anecdotal evidence that it can be used effectively and safely, as was the case with several patients in the United States.4 However, it remains to be seen whether the drug can be as effective in a larger cohort while maintaining low levels of toxicity. Several phase III trials are underway in the US and China, on both patients with a severe disease and those with mild to moderate symptoms.
Another nucleoside analog, favipiravir, might be just as close or even closer to approval than remdesivir. The guanine analog is already approved in Japan for the treatment of patients with influenza, and a clinical trial run in Wuhan with 340 patients with COVID-19 showed that it was both safe and effective at treating the disease. In that trial, it improved lung function in 91% of patients and reduced the duration of fever from 4.2 days to 2.5 days.8
A landmark study was published recently in Cell verifying that SARS-CoV-2 does, in fact, bind the ACE2 receptor, and that it requires this interaction to infiltrate host cells. The authors also found that the serine protease TMPRSS2 can prime the virus for entry, and that protease inhibitors could stop the virus from entering cells in vitro. In the study, they used camostat mesylate, a protease inhibitor already approved in Japan for the treatment of patients with chronic pancreatitis and postoperative reflux esophagitis. This means that it could potentially be tested sooner rather than later for patients with COVID-19.9
Other protease inhibitors that are currently being tested include the combination of ritonavir and lopinavir, drugs that were originally used for patients with HIV. These two drugs, also candidates for the WHO’s megatrial, likely work by inhibiting the 3-chymotrypsin-like protease of SARS, which is responsible for processing the replicase proteins of the virus.10 To keep levels of lopinavir high in the body, ritonavir is given in combination, inhibiting other proteases that may break down lopinavir.4 However, some have concerns about whether lopinavir can structurally interfere with the virus’s protease, and in one trial, the combination of the two drugs had no significant effect on the outcomes of patients with COVID-19.4,7 Conversely, a small study conducted with the protease inhibitor danopravir in combination with ritonavir showed encouraging results and might prove to be a promising therapeutic option.11
Interferons, one of the body’s most crucial cytokines to regulate the spread of viral particles, are also being considered when it comes to clinical trials for COVID-19, specifically interferon α2b and interferon β. Though they’re expected to be effective on reducing SARS-CoV-2 infectivity early on, questions have been raised about their safety in late-stage cases. Some have hypothesized that using interferons for patients with severe disease might worsen the cytokine storm that’s associated with SARS-CoV-2 infection and increase lung inflammation.5 Interestingly, interferons are not being pursued as a monotherapy by the WHO; instead, they plan to test the combination of interferon β and lopinavir/ritonavir.4
- Slater AFG. Chloroquine: Mechanism of drug action and resistance in plasmodium falciparum. Pharmacol Ther. 1993;57(2-3):203-235.
- Verbaanderd C, Maes H, Schaaf MB, et al. Repurposing drugs in oncology (ReDO) – Chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience. 2017;11:781.
- Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69.
- Kupferschmidt K. WHO launches global megatrial of the four most promising coronavirus treatments. Science (80- ). March 2020.
- Yuen K, Ye Z, Fung S, Chan C, Jin D. SARS-CoV-2 and COVID-19: The most important research questions. Cell Biosci. 2020;10:1-5.
- Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.
- Li G, Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149-150.
- Bryner J. Flu drug used in Japan shows promise in treating COVID-19. LiveScience. https://www.livescience.com/flu-drug-could-treat-coronavirus.html. Published 2020. Accessed March 26, 2020.
- Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020:1-19.
- Báez-Santos YM, St. John SE, Mesecar AD. The SARS-coronavirus papain-like protease: Structure, function and inhibition by designed antiviral compounds. Antiviral Res. 2015;115:21-38.
- Chen H, Zhang Z, Wang L, et al. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients. medRxiv. 2020:1-21.