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'Emergence of another coronavirus is inevitable'

By SWARUPA DUTT
May 13, 2020 11:42 IST
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'The worst case scenario is a rebound of the virus.'
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'The new normal therefore is test, trace and treat.'

IMAGE: The Delhi police has been trying out innovative awareness programmes to combat the coronavirus pandemic. Photograph: Manvender Vashist/PTI Photo

Virologist Dr Kamlendra Singh has reason to be excited. "Very excited," he stresses.

A week after he and his team of researchers at the Bond Life Sciences Center, University of Missouri, USA, discovered that four antiviral drugs can in fact inhibit the replication of the coronavirus that causes COVID-19 and therefore can be an imminent cure, he is now on to another cure.

"We are developing what is called RNA polymerase inhibitors of coronavirus in our lab through a collaboration with the Karolinska Institutet, Stockholm, Sweden, where I am an associate researcher," Dr Singh says over e-mail.

RNA polymerase is an enzyme that is responsible for copying a DNA sequence into an RNA sequence, during the process of transcription. Covid-19 is an RNA virus.

"We have already identified a small molecule that inhibits RNA polymerase from SARS-CoV-2 that causes COVID-19. This small molecule or its derivative can be a drug against COVID-19," he says.

But we are getting ahead of ourselves here.

A week ago, Dr Singh and his team at the University of Missouri examined whether four antiviral drugs -- remdesivir, 5-fluorouracil, ribavirin and favipiravir -- could help in treating COVID-19.

They found that all four block the virus's RNA proteins from making copies of the virus.

If replication can be stopped or inhibited, the infection can be overcome.

"When we said identified we meant that they can be effective against SARS-CoV-2 that is the causative agent of COVID-19."

He has had a head start with coronaviruses -- he has been studying them for the last 10 years.

So, in February, when hundreds of cases of COVID-19 first began being reported around the world, Dr Singh, who is also a virologist and a biochemist, began examining existing antiviral drugs for possible cures.

"These antiviral drugs have some limitations. But we are faced with a global pandemic and I believe they are worth taking a deeper look at because based on our research, we have reason to believe that all of these drugs could potentially be effective in treating COVID-19," Dr Singh, below, tells Swarupa Dutt/Rediff.com.

"As a scientist, I now feel like I'm doing my bit to help the community."

 

What are you working on now?

The coronavirus that causes COVID-19 can develop resistance to antiviral drugs, so I am conducting lab tests to see how potent the drugs are and how they react to the virus's RNA polymerase.

We are also discovering new drug-like compounds that can inhibit the COVID-19 RNA polymerase.

So, very simply, a polymerase inhibitor is supposed to block the virus replication (or making the copy of the viral genome).

The inhibitor has been identified in mid-April.

So, it is at a very early stage.

We have to test if it is safe for use, ie, we have to test the toxicity of the compound.

It is at least 5 steps away from being a drug.

Once the COVID-19 virus enters the body, it begins to make copies of itself and takes over healthy cells.

When it replicates exponentially it ultimately leads to the disease.

The more the number of replications, more the viral load and greater the chances of death.

What is the scope of your research?

The scope is drug discovery and design against viruses and cancer.

It began in 1994 and I do not see the end yet.

I have two patents for antiviral drugs and one for an anti-cancer drug. There is another one for foot-and-mouth disease virus and now one for coronavirus.

The coronavirus drug has been licensed by Shift Pharmaceuticals, Kansas, USA.

I am collaborating with this company to develop it as an anti-coronavirus drug.

The anti-cancer drug has also been licensed.

The coronavirus drug targets another viral enzyme called helicase (nsp13).

The activity of this enzyme is needed for coronavirus replication.

We, at the University of Missouri, had a patent on helicase inhibitor since 2016.

The drug was then licensed by Shift Pharmaceuticals early March 2020.

It is in pre-clinical trials, but it is hard to predict when the drug will be available in the market since there are many factors involved that we do not control.

You are a professor in which discipline? What do you teach? When does the research happen?

By training, I am a physicist.

I did my PhD in physics from Banaras Hindu University in 1994.

I am a biochemist and virologist now and I teach biochemistry at the University of Missouri-Columbia.

This research on COVID-19 drugs began on February 20, 2020, and we submitted the paper on April 3, 2020. (The study was published in Pathogens, an international, peer-reviewed Open Access journal.)

What are the four drugs you have identified -- Remdesevir, 5-fluorouracil, Ribavirin and Favipiravir – currently used to treat?

Remdesivir is a failed drug for Hepatitis C virus (HCV); it was also tried for treating Ebola, but did not work.

5-fluorouracil is an anti-cancer drug and has also been used against Coxsackievirus and Human Rhino Virus.

Coxsackievirus causes hand foot and mouth diseases (HFMD blisters/ulcers) in children but can also infect adults. Human rhinovirus causes common cold.

Ribavirin has been in clinics for a long time to treat HCV and is still used in low and middle-income countries where they cannot afford the costly treatment of HCV (sofosbuvir).

Favipiravir was approved in Japan as an anti-influenza drug. It is still being used. It has been approved in China and Italy for treating COVID-19.

Why did you think of examining these drugs in particular?

All these drugs are RNA polymerase inhibitors and have shown some inhibitory effect on other viral RNA polymerases in the past.

Are these drugs safe to use for COVID-19 patients?

There is no certainty for any drug against COVID-19, even the much-touted Remdesivir may not be safe.

We suggested that these drugs can work against COVID-19 based on the fact that they bind the RNA polymerase of SARSCoV-2.

RNA polymerase copies the genome of the virus that makes it propagate.

When you bind it, it can’t replicate and therefore is a cure against the virus.

You see, all drugs have side effects, but now, given the urgency, these drugs present curative options.

Are they nephrotoxic?

It’s really not well-defined. What we do know is that only Ribavirin can be cleared by the kidneys.

How will these drugs be used? Orally or Intravenous?

Remdesivir is given intravenous (IV), others can be given orally and as by IV.

How many months/years away are human trials for these?

Remdesivir and favipiravir are already in clinical trials for COVID-19.

The time depends upon their efficacy. Usually reports appear in 24, 48 or 96 weeks.

To the best of my knowledge 5-FU and ribavirin are not in clinical trials against COVID-19.

The COVID-19 virus can mutate 200 times, a report says. So anything that is used now as medication, can in effect be pretty much useless in a couple of months?

I am not aware of this report. However, all viruses mutate, so it is not surprising. But it is not true that the medication will be useless.

The only time medication is useless is when the treatment is suboptimal or adherence to norms is compromised.

There is no known remedy to stop the mutation in viruses.

They are obligate parasites. They evolve and adopt. HIV is a burning example of that.

If it did not mutate, we would have a permanent treatment against it.

So, how do we stay a step ahead of the virus?

That's hard to answer.

What we need is to continue research and develop treatments that are effective against all coronaviruses.

The best target in my opinion is the RNA polymerase which is the least mutated by the virus.

We must develop treatment for future preparedness.

You are a virologist. Could COVID-19 have been made in a lab in Wuhan as some reports allude?

Yes, viruses can be made in a lab.

However, there is no evidence to suggest that the SARS-CoV-2 was made in a Wuhan lab.

I do not believe it.

Coronaviruses are zoonotic (a disease that can be transmitted from animals to people or, more specifically, a disease that normally exists in animals but that can infect humans, like plague or anthrax) and I believe that SARSCoV-2, was transferred from animals to humans.

As scientist, I have to see the evidence that the current virus came from a lab.

There is none!

You have been studying coronaviruses for the last 10 years, what are your biggest learnings?

There are too many to put down, but I'll mention a few.

a. Nobody foresaw (including myself) that SARS-CoV-2 will cause a pandemic.

b. RNA polymerases of all coronavirus are conserved and should function in similar fashion. Hence the drugs developed against one coronavirus should work against others.

c. Helicase enzymes of coronaviruses are also conserved and should function in a similar fashion and hence the drugs developed against one coronavirus should work against others.

d. The research support for coronavirus should have been continued, but which was put on the backburner by many government funding agencies. That was pathetic.

e. Animals maintain the ecosystem of nature. They should not be used as a delicacy for human consumption. I guess we will learn from this pandemic.

f. Future emergence of another coronavirus is inevitable.

Why can't the medicines used for SARS-CoV and MERS-CoV be used in COVID-19 because they are also coronaviruses, and why didn't they cause the kind of havoc that COVID-19 is causing?

There are are no approved drugs against SARS-CoV and MERS-CoV.

There are many factors that can cause the increased pathogenicity of SARS-CoV-2, but nobody knows the exact answer to this question.

Scientists are working endlessly to find the answer.

But in simple terms, the current virus has evolved with mutations that make it more deadly than the previous ones.

Is COVID-19 the most virulent virus you have studied so far?

Not really.

The flu pandemic of 1918 was of similar scale.

Do HCQ and plasma therapy work?

To the best of my knowledge, HCQ does not work.

In fact, recently reported results from a clinical trial reported in the New England Journal of Medicine concluded that HCQ does not work.

A lockdown cannot go on forever. What is the worst case scenario when it opens? How does one go back to normal?

The worst case scenario is a rebound of the virus.

Life is not going to be what it was.

Life as we know it has changed forever.

The new normal therefore is test, trace and treat.

 
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