Hunt is on for drugs that hit COVID-19 where it’s most vulnerable

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The coronavirus that causes COVID-19 has spent barely 20 weeks in the human population. But, like a B-movie invader from another planet, it has wasted no time bringing our world to a standstill.

At high magnification, the virus even looks like an alien device – a spherical orb with knobby protrusions. The design is both insidious and ingenious. Inside, the virus carries everything it needs to commandeer our cells, make copies of itself and find new hosts. And it has proved even more adept than its close relative, the 2003 SARS virus, at exploiting our vulnerabilities.

Fortunately, the virus has weaknesses of its own.

In theory, that means its lethal programming can be outsmarted. The preferred way to do this is with a vaccine, something that can train our immune systems to recognize the virus and guard against it. But while multiple teams around the world are racing to develop vaccines, experts say it will likely take a year or more to reach that goal because everyone is starting from scratch.

In the meantime, clinicians are hoping that existing drugs called antivirals will prove effective against COVID-19. These are not vaccines that prevent infection, but substances that may be able to interfere with the virus after infection is under way.

Last month, the World Health Organization launched a global trial dubbed Solidarity that aims to test a range of antivirals for their effectiveness against COVID-19. Over the past week, the first Canadian patients have started on the trial.

Srinivas Murthy, an investigator at the BC Children’s Hospital Research Institute who is co-ordinating Canada’s involvement, said he hopes to soon have 700 to 800 patients enrolled in hospitals across the country.

“The more patients we have the faster we learn,” he said.

Marc-André Langlois, a virologist at the University of Ottawa, said repurposing a known drug that has already been deemed safe “is the quickest possible option for rapid deployment."

At the same time, the possibility that nothing currently available will work, or that the virus may evolve resistance to drugs over time, means that all options should be explored in earnest, including new compounds and strategies for defeating COVID-19 that will take longer to develop.

“Something that isn’t optimal now may be the only tool we have in six or 12 months,” Dr. Langlois said.

Driven by the urgency of a pandemic that has already killed more than 100 times as many people as SARS, scientists are now working on a range of antiviral drugs that correspond to different ways in which the virus can be sabotaged.

BREAKING THE INFECTION CHAIN

The life cycle of the COVID-19 coronavirus relies on hijacking the cell’s protein-building machinery to make copies of the virus. Different types of antiviral drugs are meant to interfere at different points in the life cycle.

Antiviral drugs and their target locations

A

Receptor decoys and fusion inhibitors

B

Protease inhibitors

C

Polymerase inhibitors

Spike

protein

RNA

Envelope

VIRUS

The spike protein of the virus attaches to the ACE2 receptor on the surface of the host cell

A

Cell membrane

ACE2 receptor

HOST CELL

Assisted by other proteins, the virus enters in a compartment formed from cell membrane

The cell membrane joins to the envelope of the virus and the viral RNA is released. The RNA carries the instructions for making copies of the virus

Ribosomes, the cell’s protein builders, read the RNA and produce a long chain of amino acids called a polypeptide

Polypeptides

Part of the polypeptide forms itself into protease, a cutting protein, which cuts itself out of the chain

B

Protease

Proteases cut the polypeptide chain at specific locations so that polymerase and other proteins needed to copy the RNA can form

C

Polymerase

This protein copies the RNA by first creating a mirror version which is then used to make duplicates of the original version​

Copied RNA

sequence

The polymerase replicates the complete RNA sequence and also transcribes shorter RNA sequences

The shorter RNA sequences are read by ribosomes and translated into the structural proteins of the virus

Copy of

complete

RNA

Viral

proteins

assemble

A complete RNA copy is packed into the new viral envelope

Many copies of the virus are released to infect other cells

MURAT YÜKSELIR / THE GLOBE AND MAIL

BREAKING THE INFECTION CHAIN

The life cycle of the COVID-19 coronavirus relies on hijacking the cell’s protein-building machinery to make copies of the virus. Different types of antiviral drugs are meant to interfere at different points in the life cycle.

Antiviral drugs and their target locations

A

Receptor decoys and fusion inhibitors

B

Protease inhibitors

C

Polymerase inhibitors

Spike

protein

RNA

Envelope

VIRUS

The spike protein of the virus attaches to the ACE2 receptor on the surface of the host cell

A

Cell membrane

ACE2 receptor

HOST CELL

Assisted by other proteins, the virus enters in a compartment formed from cell membrane

The cell membrane joins to the envelope of the virus and the viral RNA is released. The RNA carries the instructions for making copies of the virus

Ribosomes, the cell’s protein builders, read the RNA and produce a long chain of amino acids called a polypeptide

Polypeptides

Part of the polypeptide forms itself into protease, a cutting protein, which cuts itself out of the chain

B

Protease

Proteases cut the polypeptide chain at specific locations so that polymerase and other proteins needed to copy the RNA can form

C

Polymerase

This protein copies the RNA by first creating a mirror version which is then used to make duplicates of the original version​

Copied RNA

sequence

The polymerase replicates the complete RNA sequence and also transcribes shorter RNA sequences

The shorter RNA sequences are read by ribosomes and translated into the structural proteins of the virus

Copy of

complete

RNA

Viral

proteins

assemble

A complete RNA copy is packed into the new viral envelope

Many copies of the virus are released to infect other cells

MURAT YÜKSELIR / THE GLOBE AND MAIL

BREAKING THE INFECTION CHAIN

The life cycle of the COVID-19 coronavirus relies on hijacking the cell’s protein-building machinery to make copies of the virus. Different types of antiviral drugs are meant to interfere at different points in the life cycle.

Spike

protein

Antiviral drugs and their target locations

A

Receptor decoys

and fusion inhibitors

RNA

B

Protease inhibitors

Envelope

C

Polymerase inhibitors

VIRUS

The spike protein of the virus attaches to the ACE2 receptor on the surface of the host cell

A

Cell membrane

ACE2 receptor

HOST CELL

Assisted by other proteins, the virus enters in a compartment formed from cell membrane

The cell membrane joins to the envelope of the virus and the viral RNA is released. The RNA carries the instructions for making copies of the virus

Ribosomes, the cell’s protein builders, read the RNA and produce a long chain of amino acids called a polypeptide

Polypeptides

Part of the polypeptide forms itself into protease, a cutting protein, which cuts itself out of the chain

B

Protease

Proteases cut the polypeptide chain at specific locations so that polymerase and other proteins needed to copy the RNA can form

C

Polymerase

This protein copies the RNA by first creating a mirror version which is then used to make duplicates of the original version​

Copied RNA

sequence

The polymerase replicates the complete RNA sequence and also transcribes shorter RNA sequences

The shorter RNA sequences are read by ribosomes and translated into the structural proteins of the virus

Copy of

complete

RNA

Viral proteins assemble

A complete RNA copy is packed into the new viral envelope

Many copies of the virus are released to infect other cells

MURAT YÜKSELIR / THE GLOBE AND MAIL

HIDING THE KEYS

A coronavirus get its name from the forest of proteins that stick out of its viral envelope like the points on a crown. These are its spike proteins. In COVID-19, they bind to a receptor on the surfaces of cells known as ACE2 (angiotensin-converting enzyme 2). It’s the lock-and-key system by which the virus first latches onto and then gains entry into its target.

Because the SARS virus also latches on to ACE2, researchers have already been looking at how to block this interaction. In some cases, strategies that were devised but never tried because the SARS pandemic ended are now being dusted off and given a second look.

Josef Penninger, a molecular immunologist at the University of British Columbia, was among the first to show the link between ACE2 and SARS. Together with colleagues at the University of Toronto, he has developed a drug that is a synthetic version of ACE2.

It can act as a decoy that the virus will bind to instead of to host cells. The drug, called APN01, went through early phase trials prior to the emergence of COVID-19. Now a clinical trial with COVID-19 patients conducted by Apeiron Biologics, a Vienna-based biotech company, is about to commence in Europe.

“We are targeting severe or critical patients,” said Haibo Zhang, a staff scientist at St. Micheal’s Hospital in Toronto who was involved in the development of the drug. In fact, much of the groundwork was already in place last month for a clinical trial of the drug in China, but the rate of new infections there has slowed so much that the team had to switch tracks.

In Ottawa, Dr. Langlois is leading a different project that includes looking at ways to intercept the virus using its affinity for ACE2. But he notes that the risk of this approach is that the virus will eventually evolve a slightly different spike protein tip against which decoys are less effective.

As an alternative, he is working with “single domain antibodies” – tiny molecules that can be engineered to fasten on to parts of the spike protein that are hard for decoys to access. These regions face no evolutionary pressure to change because the body’s immune cells can’t see them. One such area is crucial for enabling the fusion of the virus with the host cell membrane, which makes it an attractive target for halting infection.

Instead of blocking the key, other teams are looking at drugs that change the lock – in other words, altering the way ACE2 and other enzymes at the cell surface interact with the virus. The anti-malaria drug, hydroxychloroquine, may prove to be one such candidate though evidence for this is mixed. That did not stop U.S. President Donald Trump from declaring the drug a “miracle” last week, much to scientists’ alarm. Hydroxychloroquine is among the drugs being tested in the WHO’s Solidarity trial.

BLUNTING THE SHEARS

Once the contents of the coronavirus are in a host cell, its long strand of RNA uncoils and makes its way to a ribosome, one of the cell’s protein production factories.

The RNA contains all the information needed to produce new virus. The ribosome blindly reads these instructions and spits out a vast string of viral proteins that start out joined together like the pieces of a plastic model-making kit. Before a copy of the virus can be assembled, those individual parts have to be separated from one another.

At the leading end, the string forms itself into two enzymes called proteases that have the ability to cut themselves away from the rest of the string and then cut apart other proteins. If the proteases are prevented from cutting, the virus will be stopped in its tracks.

Drugs called “protease inhibitors” are designed to do just that. Two such drugs, called ritonavir and lopinavir, have previously been used in combination to combat HIV. Now they are among the antivirals that are being tested in Canada as part of the Solidarity trial.

Researchers are also looking at other options, including a protease inhibitor originally developed at the University of Alberta, which has since been used to treat feline coronavirus.

Joanne Lemieux, a researcher at the university who specializes in protein structure, is leading a federally funded project to determine precisely how the three-dimensional shape of that inhibitor allows it to fit into the coronavirus protease and block the region that would normally be used to cut other proteins.

“We’ll see exactly how the inhibitor sits into the pocket" of the enzyme, Dr. Lemieux said.

Once that is understood, the next step will be to design a variation of the inhibitor that would fit equally well into the COVID-19 protease, thereby derailing the virus’s protein assembly line.

JAMMING THE COPIER

The central step in the coronavirus’s life cycle is the copying of its RNA. Duplicates are destined to be packed into newly assembled viral capsules that will then find their way to other hosts.

The copying system of a coronavirus is prone to error, which, ironically, is one of its strengths because some of the mistakes it makes will spawn variants that are more effective pathogens. Even so, the copying still needs to produce a complete strand of RNA along with shorter segments that provide the instructions for building spike proteins and the other components of a complete virus.

The copying is done by another viral enzyme called polymerase, which draws on the cell’s raw materials to build new RNA. One way to defeat it is to feed the polymerase with incorrectly shaped building blocks that stop the process just like a paper jam stops a photocopier. The drug remdesivir, originally developed by the California-based pharmaceutical company Gilead Sciences to treat Ebola, is an example of this strategy.

Matthias Gotte, a biochemist who specializes in antiviral drugs at the University of Alberta, is among those leading the study of how remdesivir operates in coronaviruses. In a recent study of the drug in the MERS (Middle East respiratory syndrome) virus, Dr. Gotte and his colleagues found the drug was more attractive to polymerase than the regular RNA building blocks that are needed to construct the viral genome.

“We’ve shown the drug binds a little bit better than the natural counterpart and this is a very good sign,” he said.

The team is now working to determine if remdesivir, among other polymerase inhibitors, has a similar effect on the COVID-19 coronavirus. Remdesivir is also one of the drugs beings tested in Canada as part of the Solidarity trial.

CALMING THE STORM

Some drugs do not affect the virus itself but may mitigate the body’s reaction to it. It is now clear that some of the most severe cases of COVID-19 are caused by inflammation due to an overaggressive response by the immune system. At the cellular level, this is called a cytokine storm. Some drugs that are meant for other purposes, including heparin, are now being investigated for signs of being able to calm the immune response.

The challenge with any drug is to find something that works and that excludes dangerous side effects. Even then, if the virus has progressed too rapidly, it’s likely no drug can stop it. That is why antivirals should not be thought of as cures but as treatments that have the potential to shave down the case fatality rate of COVID-19, even if only by a small fraction.

“When you scale that out to the whole epidemic, that amounts to possibly tens of thousands of lives," Dr. Murthy in British Columbia said.

What is most important, scientists say, is to conduct trials that are large, rigorous and controlled – especially in the face of the extraordinary situation the world faces because of the COVID-19 pandemic. Otherwise, unsafe or ineffective drugs will waste precious time and resources and possibly claim the lives of some who would have recovered from COVID-19 on their own.

During an online presentation this week, Dr. Penninger paused from his technical talk to stress the point.

“Even in this chaos it’s important that we don’t put aside the things that have always helped us," he said. "Science-driven clinical studies.”