Congrats to Jennifer Doudna and Emmanuelle Charpentier for winning the Nobel Prize in Chemistry, 2020. The idea to edit DNA sequences and…
Teaming treatments has long been a strategy to quell cancer, override mutations, and fight viruses. Will that be a winning strategy against SARS-CoV-2, the virus that causes COVID-19?
Surgery, chemo, and radiation are the traditional triple-punch against cancer, with more recent targeted therapies moving to the frontline. The same road has unfolded for cystic fibrosis (CF).
Fixing Errant Ion Channels
The first treatments for CF were simple: pounding on the chest to dislodge sticky mucus, sprinkling digestive enzymes on applesauce, and using old drugs to combat inflammation and infection.
The new CF drugs that have revolutionized treatment for most patients are small molecules that interact with the malformed ion channels that lie behind the disease. The channels are tiny tubes built of cells festooned with proteins that regulate the balance of water and salts in many body parts – hence the diverse symptoms of breathing difficulty, poor fat digestion, salty sweat, lung infections, and male infertility.
The new drugs work in three related ways.
The first, ivacaftor (Kalydeco), approved in 2012, treats the 5 percent of patients with a certain mutation, G551D. The drug unfurls and refolds ion channel proteins that stay stuck at the cell surface from within, like hitting a ceiling.
In 2018 came a second drug, tezacaftor, the duo dubbed Symdeko and prescribed for patients with two copies of the most common mutation. The second drug anchors ion channels at the cell surface long enough for them to allow salts back and forth.
In 2019 came the third CF drug, elexacaftor (Trikafta), for patients who have one common mutation plus another that shortens the ion channel proteins. The third drug enables cells to bypass that mutation.
The daily trio of pills vanquishes CF symptoms, although not the underlying mutations that can pass to the next generation.
Three Strikes and HIV/AIDS is Out
To develop the first HIV/AIDS drugs, researchers at the National Institutes of Health reached into their bag of pharmaceutical possibilities to see what made sense to cripple viral enzymes.
The first drug to emerge was azidothymidine (AZT), made famous in the play Rent when the main characters, circa early 1980s, set their watch alarms to be sure to take their doses.
AZT was a mediocre cancer drug from 1964. But it also attacks reverse transcriptase, the enzyme that HIV uses to copy its genetic material, RNA, into DNA in order to commandeer human cells. FDA approved AZT for HIV/AIDS in 1987, and two more reverse transcriptase inhibitors followed.
As AIDS patients became resistant to AZT, researchers sought other viral targets.
Investigators at the National Cancer Institute turned to HIV protease, leading to a new class of HIV drugs by the 1990s. Protease inhibitors block viral enzymes that cut proteins down to workable sizes. Drugs from two classes are better than from one.
In the early 2000s came the third pharmaceutical strike against HIV, the fusion inhibitors. These drugs block a glycoprotein on the virus’s surface that it uses to attach to our cell membranes. The triple cocktail had arrived.
Blocking Hepatitis C Virus
Similar to treating HIV/AIDS, drug combos to treat hepatitis C work in three general ways:
• Protease inhibitors
• Polymerase inhibitors are metabolized into a chemically altered version of the RNA building block uridine (“U”). The virus’s replication enzyme incorporates the booby-trapped U and shuts down, like placing a period in the middle of a sentence or a snag in a zipper. No new virus.
• NS5A inhibitors block formation of a viral protein (NS5A) that encases the replication machinery in protective bubbles that invade our cells, where they pump out virus. No new virus.
The triple whammy works, with specific combos tailored to genetically distinct strains of the virus.
Until vaccines can be widely distributed, anti-viral drugs are stepping in to shorten the course of the illness and dampen symptoms.
“Vir” at the end of the generic name of a drug indicates that it’s an anti-viral. Such a drug intervenes in the infection process, blocking viruses from entering our cells or impairing their ability to replicate and burst from the cell.
Anti-virals have several benefits, clinically speaking. Some are easier-to-take daily pills, and they tend to work on people of all ages. In addition, many anti-virals are broad spectrum, useful against different pathogens. That’s why Remdesivir received emergency use authorization so quickly, in May, to treat COVID-19. It was developed in 2014 to fight Ebola, but also works against Nipah virus, respiratory syncytial virus, and the coronaviruses behind SARS and MERS.
Like the hepatitis C drugs, Remdesivir delivers an altered version of an RNA building block, adenine, halting viral replication. Specifically, the drug cripples RNA polymerase, the enzyme that adds subunits to an RNA.
But not all older anti-virals can be repurposed. Lopinavir, an HIV/AIDS protease inhibitor, didn’t work for severe COVID-19. And a small, short study of the hepatitis C protease inhibitor danoprevir was safe in COVID patients, but hasn’t been tested for efficacy yet.
A second approach to treating COVID-19 is to deploy antibodies. These proteins bind to parts of the virus in ways that prevent them from binding to and entering cells.
The body normally makes many different antibodies to a pathogen, each type targeting a different part of the surface (an antigen). That’s called a “polyclonal” response. Convalescent plasma delivers a mixed bag of antibodies – polyclonal – from recovered patients.
A monoclonal antibody, in contrast, is a single antibody type, made in a laboratory. They were initially produced in mouse abdomens until the practice was discontinued because it hurt them.
The “REGN-COV2 cocktail” from Regeneron is a double monoclonal with a one-two punch. It hits two areas of the “receptor binding domain” where the virus binds cells (at the ACE2 receptor), which I explain here.
To sum up, antibodies keep the coronavirus out of our cells, and should they enter, Remdesivir (and other antivirals on the way) block viral replication. What’s next? Perhaps a therapeutic, new or repurposed, that directly attacks the coronavirus? I took a look at ClinicalTrials.gov, searching under COVID-19 and “drugs phase 3.”
More than 500 entries popped up for phase 3-ers, 2300+ if the search is widened to “COVID-19 and treatment.”
Of the 500 approaches, many combine existing drugs. A promising candidate, in 37 clinical trials, is the antiviral favipiravir, already used to treat influenza in China and Japan but not approved in the US. Like Remdesivir, it inhibits RNA polymerase, but has a different chemical structure. So that seems to be a frontrunner – I hope something novel comes along too.
The stories of conquering other infectious diseases, or at least making them survivable, bodes well for defeating COVID-19. A “triple cocktail,” like we have for HIV/AIDS and hepatitis C, may be coming soon for SARS-CoV-2. Stay tuned …