Expert Q&A tackles headline-making drugs in the fight against COVID-19

Catherine Mills
April 15, 2020
Dr. Patrick Woster of the Medical University of South Carolina
Dr. Patrick Woster, SmartState Endowed Chair in Medicinal Chemistry and chair of the Department of Drug Discovery and Biomedical Sciences at MUSC’s College of Pharmacy

Amidst the COVID-19 pandemic crisis, people isolating at home find themselves overwhelmed by the constant stream of information – often conflicting – released by news outlets. The past few weeks have offered countless headlines focused on drugs being used to fight SARS-CoV-2, the virus at the center of this pandemic. 

What are these headline-making drugs, and how are they being used to treat this virus? Why is the antimalarial drug hydroxychloroquine being studied as a potential treatment? Why is the UK’s National Health Service advising patients diagnosed with COVID-19 to take paracetamol, its counterpart to acetaminophen, instead of ibuprofen? 

These questions, and others, are on the forefront of people’s minds as they contemplate how to remain safe from the virus.

In an effort to clear up some of the confusing messages that surround pharmaceuticals currently dominating news cycles, MUSC’s Patrick M. Woster, Ph.D., the SmartState Endowed Chair in Medicinal Chemistry and chair of the Department of Drug Discovery and Biomedical Sciences at MUSC’s College of Pharmacy, agreed to share his thoughts in an informative Q&A. “After all,” he explained, “promoting patient health is the reason I’m in this business.”

“It remains controversial whether hydroxychloroquine has potential in treating COVID-19. Researchers think hydroxychloroquine might be acting as an entry inhibitor. Entry inhibitors act by preventing the virus from recognizing the host cell or by keeping it from pushing its way into the cell."

-- Dr. Patrick Woster

Researchers at MUSC are involved in numerous efforts to uncover chinks in the virus’ armor, including drug studies aimed at combating COVID-19. Through his work as a drug discovery researcher at MUSC, Woster is particularly well qualified to provide a medicinal chemistry perspective on pharmaceuticals making news today. 

Woster and collaborator David Edwards, Pharm D., of the University of Waterloo, are perhaps best known for their discovery of the compound in grapefruit that alters the absorption of certain drugs, the science behind the prescription warning label that reads “Do not eat grapefruit or drink grapefruit juice while taking this medication.” Although his primary expertise is in the cancer field, it is his work with antimalarials, developing agents with some promise against strains of the malaria parasite that don’t respond to drugs like hydroxychloroquine, that provides him specific insight into today’s issues. 

In this interview, Woster helps the public understand the science behind conflicting information and how those chinks in the virus’ armor might well provide a target for either repurposed or newly developed drugs. 

One drug making headlines right now in the fight against COVID-19 is hydroxychloroquine, a drug typically used for treating malaria. How does this drug work, and why is there speculation that it could be used against the virus causing COVID-19?

Hydroxychloroquine disrupts the metabolism of human hemoglobin by Plasmodium falciparum, the parasite that causes malaria. The drug causes a buildup of toxic metabolites that kill the parasite. Because this enzyme is present in the parasite but not in humans, the drug is not toxic to the patient. 

It remains controversial whether hydroxychloroquine has potential in treating COVID-19. Researchers think hydroxychloroquine might be acting as an entry inhibitor. Entry inhibitors act by preventing the virus from recognizing the host cell or by keeping it from pushing its way into the cell. 

The COVID-19 virus recognizes the host cell through an enzyme called ACE 2, which is involved in regulating our blood pressure. There’s a small segment of ACE 2 that protrudes from the cell, and the virus has a high affinity for this segment. The virus sticks to the enzyme and gets pulled inside the cell.

Lung cells have higher levels of ACE 2, which is one reason why COVID-19 is a respiratory virus. Other areas in the body also have high concentrations of cells with this ACE 2, including the digestive tract, and these are the areas in the body where problems caused by this virus arise. 

Just to clarify, ACE inhibitors, commonly prescribed for the control of hypertension, would have no effect on the ability of the virus to recognize cells. Recognition is the only role ACE 2 plays in the viral life cycle. ACE inhibitors do not inhibit ACE 2 and work on the previous enzymatic step – ACE is different from ACE 2.

Recently, a man died after taking chloroquine phosphate to prevent COVID-19. Is hydroxychloroquine the same thing, and is it safe?

That was a formulation situation. A couple took tablets intended for use in cleaning aquariums and ponds. While these tablets did contain chloroquine phosphate, a solvent used to treat parasitic infections in fish, they also contained other ingredients that were toxic when taken internally. Sadly, they essentially poisoned themselves with a household cleaning product not meant for ingestion. 

Hydroxychloroquine, taken in the correct dose, and when prescribed by a physician, is actually a very safe and effective drug that has been used for decades. It was derived from quinine, which is isolated from the bark of the cinchona tree, and people have been using that for hundreds of years.

A recent publication indicated that an FDA-approved, broad-spectrum anti-parasitic drug, Ivermectin, showed anti-viral activity toward COVID-19. How might this drug differ from hydroxychloroquine?

Ivermectin is used as an antihelminthic and works by disrupting chloride channels in parasitic insects and worms. This results in hyperpolarization in the cells in their nervous system and eventually kills the parasitic organism. It is not toxic in mammals, including humans. In the virus, Ivermectin is another entry inhibitor that prevents the virus from penetrating into the cell nucleus. It appears to block the protein complex that must form to allow the virus to enter the cell nucleus through the nuclear pore complex, so this is a different mechanism of entry inhibition. It may prove to be effective at some point but is unlikely to be prescribed based on one in vitro study.

Why is it important to test whether existing drugs such as hydroxychloroquine, an antimalarial drug, and remdesivir, a drug created for the Ebola virus, work against COVID-19?

It will take time to develop a vaccine against the virus, though everything is being done to speed up the approval process. Development of a small-molecule inhibitor will take much longer. In the meantime, repurposing existing drugs, such as hydroxychloroquine, is a much faster approach. Repurposing drugs for off-label use will likely be the quickest way to find a treatment. I see no reason why physicians can’t prescribe a currently available drug if they have some evidence that it actually works, and they feel the risks associated with the disease outweigh those of the cure. For instance, there are reports that both chloroquine and hydroxychloroquine, in addition to the antibiotic azithromycin, prolong QT interval, raising concerns about the risk of arrhythmic death from individual or combined use of these medications in patients with pre-existing risk factors for cardiac arrhythmias. A prolonged QT can potentially cause fast, chaotic heartbeats, which could trigger a sudden fainting spell or seizure, and in some cases, the heart can beat erratically for so long that it causes sudden death. Prescribers would have to factor in these concerns. There are also other variations of this treatment, such as hydroxychloroquine used with the antibiotic azithromycin and the mineral zinc, all of which are currently in clinical trials. 

If hydroxychloroquine turns out to be effective and is approved by the FDA for use against COVID-19, it could be widely distributed. For example, Mylan Pharmaceuticals has already reinitiated the manufacturing of hydroxychloroquine to provide 50 million tablets that could treat 1.5 million patients. To put dose availability in perspective, on April 14, there were more than 582,000 confirmed cases in the U.S., according to Johns Hopkins University.

Remdesivir was developed by Gilead Sciences during the Ebola crisis. Ebola is not a coronavirus, but it is similar in that it is a single-stranded RNA virus. Remdesivir was developed to prevent the Ebola virus from making copies of its viral RNA. Scientists think this compound could work with COVID-19 as well. Gilead has given this drug out for clinical trials and will quickly evaluate whether or not it works to halt the progression of infection.

Chemical structure of hydroxychloroquine Chemical structure of remdesivir
Chemical structures of hydroxychloroquine (left) and remdesivir (right). Images courtesy of Dr. Patrick Woster.

The UK’s National Health Service is advising physicians to treat COVID-19 with paracetamol, the equivalent of acetaminophen, instead of ibuprofen. Is there reason to favor acetaminophen to ibuprofen in these patients?

Most of the pain and fever you get when you are sick is from inflammation caused by substances released by the body to fight the infection. Ibuprofen inhibits the synthesis of these substances and reduces inflammation and pain. It can also reduce fever. Acetaminophen is not an anti-inflammatory, but it is better at reducing fever, and it alleviates pain by a different mechanism than ibuprofen. If you want to reduce your fever, then you take acetaminophen. If you want to reduce fever and block the synthesis of the nasty elements that are released in response to a virus, then you take ibuprofen. But in either case, you’re just treating symptoms.

One potential issue with taking ibuprofen for COVID-19 is that scientists have theorized that ibuprofen could increase the number of ACE 2 receptors on the host cell, but that has not yet been proved. 

 

About the Author

Catherine Mills
Catherine Mills is a Ph.D. student with an interest in medicinal chemistry and is working in Dr. Patrick Woster’s laboratory, which is focused on the design, synthesis, and biological evaluation of epigenetic modulators that serve as antitumor and anti-inflammatory agents in cancer and periodontal disease.

Keywords: COVID-19