Going
viral

As countries around the world battle the COVID-19 pandemic, an Otago-led project is working to develop new classes of antiviral drugs, drawing on national and international expertise to meet a vast unmet need.

A push to develop new classes of antiviral drugs being led out of Otago and drawing on scientific expertise from around the country and overseas has been awarded a $13.5 million MBIE Endeavour Fund grant.

New Frontiers in Antiviral Development project leader Professor Vernon Ward (Microbiology and Immunology) says an important part of MBIE funding is the focus on developing discoveries so that they can be taken to market.

Although the commercial imperative is strong, there is also a large unmet need in the antiviral space which continues to grow with the appearance of new virus strains such as the recent COVID-19 outbreak, which began in the Chinese city of Wuhan and is now spreading internationally.

“There are a lot of viruses out there for which there's no treatment. On top of that, just like you talk about antimicrobial resistance from bacteria, we get antiviral resistance from viruses. So you generally need combination therapy or a range of antiviral options.

“A classic example would be influenza. One group of drugs is called the amantadines, but flu strains got so resistant to them they're not recommended anymore. So there is an urgent need for new treatments,” he says.

“It is what MBIE would call an unmet need. There's a vast market out there for antiviral agents.”

Another example is measles, Ward explains.

“We also want to target things that nobody's targeted before because we think that will open up new opportunities to get that combination of drugs to avoid resistance.”

“You should vaccinate against this disease – that's a no brainer. In parts of Africa a measles outbreak has caused over 6,000 deaths and the recent outbreak in Samoa shows how devastating this disease can be. But if people have caught measles, wouldn't it be great to be able to treat them and stop them dying from it?

“There's a huge market there for antiviral agents and that's what we're looking for. There are many people who would benefit from having an agent to treat the disease once they've got it.”

In fact, the market for antivirals is expected to reach around US$63 billion next year.

Ward says they are particularly interested in developing antivirals that have broad spectrum potential. “So drugs that don't just target one virus, but potentially multiple viruses. It's a different paradigm to what's been done in the types of antivirals that have been developed previously – to open up new doors of what antivirals might look like.”

These antivirals can target specific components that the virus uses to replicate – things that are different about them that you don't find in the host cell. That ability to differentiate between host and virus is vital, Ward explains.

“A virus has a very intimate relationship with its host. It's replicating inside the cells of the host using the machinery of those cells to replicate, so the difference between the virus and the host can sometimes not be a lot – and you're trying to target things inside cells as the virus is replicating.”

To develop drugs capable of tackling new targets requires a strong team of people and he has brought together top researchers.

“You've got to have virologists – that's what I do – but you've also got to be able to have the people who can work in cell culture and do the cellular and molecular type work of understanding the proteins and molecules in the virus that you're trying to target, and interrupt and affect their ability to manipulate a host cell.”

Professor Vernon Ward: “I'm a card-carrying virologist. I grow viruses, I work with viruses, I study their molecular and cellular biology – which is the detail and understanding needed for this sort of work.”
Photos: Sharron Bennett

A lot of information about the COVID-19 virus and the disease it creates has become available in a short period of time and that, Ward says, shows the value and importance of a team approach when tackling viruses.

“You've got to have people who are able to understand the structure of proteins and do the structural biology. You've got to have access to all sorts of different chemical compounds for your screening assays. How do you know if a potential drug interacts with one of your target proteins?

“Once you've got a lead, how do you develop that into something that actually can be used medicinally? Sometimes you get things that work, but are toxic and hence can't be used, so you've got to be able to modify them,” says Ward.

“It's a matter of getting the right team together and that's what this grant is about.”

Alongside Otago researchers, they have people from the University of Auckland, the Ferrier Institute at Victoria University Wellington, ESR, Glycosyn – a New Zealand company that makes medicinal-grade drugs – as well as structural biologists and medicinal chemists for all the development and testing work that needs to go on.

It is something of a who's who featuring the likes of medicinal chemist Professor Dame Margaret Brimble, whom Ward describes as one of New Zealand's premier scientists in this area.

“We've now got a team in New Zealand that's capable of developing antivirals and we think there are vast opportunities that will benefit a lot of people, but also be viable commercially.”

“We've got really good collaborations offshore, such as into the Albert Einstein College of Medicine in the USA, the University of Southampton UK, and we have biotechnology company linkages.”

Group members all share a strong track record of getting income from intellectual property, have drugs in trial right now and have experience launching start-up companies, says Ward.

“There's been about $200 million of intellectual property out of the researchers within this group in the last five years, so the capability to do this is there. What we've never done is bring them all together in one place to tackle viruses.

“We have enough leads through previous funding and other work to know where we're going with that. We also want to target things that nobody's targeted before because we think that will open up new opportunities to get that combination of drugs to avoid resistance.”

Ward says it is important to think about the commercial side as you are developing a treatment.

“The cost of bringing something to the medical treatment market is large. If you don't have a commercial position, no one's going to give you the money to do it. That's what so many people forget.

“I do basic research where I publish what I find, and I like doing that. But how do you go from bench to bedside? Part of going bench to bedside for drugs, at least, is being able to get a commercial proposition on them,” he says.

“If it is not financially viable to do all the testing and development then no one will ever get helped by it. You can argue about whether that's good or bad – but that is the reality at the moment.”

Once they develop a reagent against one virus, they will also try it against others.

“We have the capability to develop reagents against a range of viruses. That will benefit people and hopefully also New Zealand as a whole.”

Looking further down the track there is also the possibility that some of the things they develop for human disease could also be used to combat animal disease.

Ward stepped down from five years as Dean of the School of Biomedical Sciences at the end of last year to concentrate on the new project.

A PhD student at Otago in the mid-1980s, his interest in working on viruses took him to Oxford for his first postdoc and then to the University of California, before eventually returning to Dunedin.

“I've worked on viruses for the better part of 35 years now. All sorts of different viruses – insect viruses, arthropod transmitted viruses, human viruses – a whole raft of viruses over my career.”

It means he has a broad virology background, ideal for the role he is now tackling.

“I'm a card-carrying virologist. I grow viruses, I work with viruses, I study their molecular and cellular biology – which is the detail and understanding needed for this sort of work.”

Otago has a long tradition in virology and Ward sees it as being in a strong position thanks to a number of very good virologists across several departments and sectors of the University.

“When tackling viruses, you've got antiviral drugs, vaccines and public health. They are all areas where Otago has strengths,” adds Ward.

Mark Wright

Professor Vernon Ward with assistant research fellows Sasheen Dowlath and Geena McKenzie-Goldsmith: “There is an urgent need for new treatments