Why are there so few drugs to treat viruses?

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

The discovery of antibiotics revolutionised medicine more than 100 years ago. Combined with vaccines, these effective treatments transformed human existence from one where infectious disease was the leading cause of death, to a world where most people die of age-related illness. As the world watches coronavirus case numbers surge, people are asking why we have so many effective drugs for treating bacterial diseases, but relatively few for combating viruses?

Associate Professor Stuart Ralph is Acting Head of the Department of Biochemistry and Molecular Biology in the School of Biomedical Sciences. Dr Craig Morton is a Departmental Senior Research Fellow, based at the Bio21 Molecular Science & Biotechnology Institute. These University of Melbourne biomedical scientists sat down with Dr Andi Horvath to zoom chat about their work and the world’s search for a drug to treat – or prevent – coronavirus.

ANDI HORVATH
Gentlemen, tell me about the virus because drugs block things or they change the biochemistry of what’s going on. Take me down to the level of what’s happening with the virus and the cell, so I can then understand drug control.

STUART RALPH
Coronavirus itself doesn’t have a cell. It’s a virus that’s made out of a genome and a few proteins and a lipid coat that’s wrapped around the genome. Unlike us, its genome isn’t made out of DNA, it’s made out of another string of instructions that’s called RNA. That virus infects our cells and replicates within them. That replication and the distribution throughout the body is what eventually causes the disease.

ANDI HORVATH

So my understanding is, the virus gets into our lung cells in some manner - it squashes its way in. It replicates inside. It makes more of itself using our cells’ mechanisms. Then it gets out to sort of do world domination and infect other people’s lung cells. Is that right?

STUART RALPH
Yeah, that’s right. The virus needs to be able to make lots of copies of itself in order to be able to stay alive. Those copies are coughed out when we cough or put saliva on a surface. They can infect another person where they will then replicate millions of times again. They can infect our lung cells directly, but they can also infect other cells in our body.

ANDI HORVATH
Okay. If you’re designing a drug to try and halt it in its tracks, where do you attack it? Do you attack it at its physical parameters of its lipid fatty coat as you were referring to, or do you attack it when it’s trying to get in or out or replicating? Tell us about drug design for a virus.

STUART RALPH

I think this is the real killer when it comes to viruses. There just aren’t that many different ways that we can think of to attack viruses. We’ve got lots and lots of drugs for parasites and bacteria, which have lots of potentially susceptible targets, but in the case of viruses, there aren’t that many things that they actually do. So we’re limited to a handful, maybe only a dozen, discrete processes that we can think of to interrupt, and that that interruption would cause the virus to either stop replicating or our bodies to not get sick because they’ve got virus inside them.

CRAIG MORTON
A key point about the drug discovery process in this context is that you’re trying to find a compound that only works on the virus. You’re trying to find a weakness that the virus carries that our bodies don’t. So, you can come up with drugs that will target something specific to the virus. Because they have only a few genes compared to a complex organism like us or even a bacteria, there are only very few targets available. Things like the physicochemical properties of a viral particle, you can target that through basic hand hygiene; washing your hands with soap will kill the viral particle very efficiently. But you can’t do that inside your body so the physicochemical targeting, the breaking the viral particles that way, really doesn’t work as a drug treatment, only as a – effectively as a sterilisation of surfaces or skin approach.

STUART RALPH

I think we could break down the ways that we could kill a virus into a few broad categories. We can stop the virus from recognising our cells and getting in. We can stop the virus from replicating once it’s inside the cell. We can stop the virus from getting out of the cell intact again. Then the other thing that we can do is to potentially modulate our own immune systems that make us at least less sick when we are infected by viruses.

ANDI HORVATH
So there’s four avenues I imagine around the world research is focusing on. Give us some context of other viral diseases. How have we tackled drugs against viruses in other situations other than COVID?

STUART RALPH
Well in recent years, there have been really very promising developments against a number of the big human viruses. HIV is one. Hepatitis C is another. In both of those areas, we’ve seen really tremendous advances over the last couple of decades, where we’ve seen a number of really quite effective drugs come onto the market. In some cases – in the case of hepatitis C, for the first time offering actually a radical cure. But there’s a bunch of other viruses, some of which are really big world killers, that we really don’t have drugs for against. Rotaviruses are one category that kill somewhere in the order of half a million children through diarrhoea every year, and we don’t have any treatment against rotaviruses whatsoever. Dengue’s another one that kills an enormous number of people in tropical areas of the world. Again, we don’t have any very good effective treatments – any good antivirals that really help us to combat dengue. So although there’s been some progress over the last few decades, there are really enormous holes to fill when it comes to viruses where we don’t have any treatment options.

CRAIG MORTON

If I can just add to Stuart’s comments there, a lot of the viral diseases where we have good drugs are chronic infections, things like HIV or hepatitis C where it’s a slow progressive disease, the virus is in you for a long, long time. Acute infections, things like common cold and influenza, and in this case, SARS – so coronaviral infections, happen very quickly and either resolve very quickly, you get better, or in the case of the occasional patient, you have horrible catastrophes, and they get very, very sick indeed. It’s easier to target these long slow burn infections where there’s plenty of time for your drugs to work against the virus than it is for these sudden rapid onslaught diseases which hit you very quickly and then are gone. Often you don’t show symptoms until it’s too late for a drug to have a reasonable chance of success before the virus has either cleared or you’re in serious medical trouble.



ANDI HORVATH
Wow. So that really clarifies why some viral diseases we’ve sort of got on top of and why we can’t get on top of, at the moment, on others. Just enlighten me with the HIV and Hepatitis C. At what point do the antiviral drugs work? Do they work at the getting in, replicating, or getting out, or the immune system? Where do those drugs have an effect?

STUART RALPH
The ones that I’m familiar with stop viral replication. They can do that in a number of different ways. One of the things that the virus needs to be able to do is to copy its own genome, its genetic instruction set. Some of these quite effective antivirals work by poisoning that replication system. The other way that some of those drugs work is that once those instructions are read into what’s called a protein, in many cases, viruses have a tricky way of making one protein and then chopping it up into smaller parts. Those smaller parts of the proteins then fulfil different roles in the cell. They use what’s called a protease, which is an enzyme that chops the protein up into smaller functional subunits, and some of the drugs that work against diseases like HIV or Hepatitis C which have been quite effective, work against those viral proteases.

ANDI HORVATH

Okay, so we’re in new territory with these fast replicating viruses. Is it a numbers game? Is that where the target needs to be?

CRAIG MORTON

It’s a question that’s hard to answer at this point in time. For example, the common cold, that’s sort of proverbial, that there’s no cure for the common cold. Common cold, the symptoms you get, are caused by a large number of different viruses. There’s a family of viruses called the rhinoviruses which cause about 70 per cent of common colds. Then other diseases that have the same symptoms are caused by a virus called respiratory syncytial virus caused by a family of coronaviruses, in fact. Curing the common cold is extremely difficult because it’s not just one disease. There are drugs that will target the rhinoviruses, but the question there is the timing. By the time you’re showing symptoms, treating the viral illness is almost pointless; you’re getting better already.



What we don’t know is how well you need to suppress the viral replication, the growth of the virus, inside a person, to have a clinically significant improvement in their outcome. It may be that reducing the viral replication by 10 per cent is enough to reduce hospitalisation or reduce the chance of someone becoming extremely sick. Those sorts of things, particularly for coronavirus at the moment, we really have no feel for what level of viral suppression is needed to give you a useful medical outcome.

ANDI HORVATH
We can’t take antivirals as a preventative, can we?

STUART RALPH
We don’t really know the answer to that question yet. There are some circumstances where people do take antivirals as preventative. HIV is one of those areas. In the case of coronavirus and case of SARS-2, or COVID-19, we’re not really sure whether or not you can take a preventative dose of drugs, or what we call a prophylactic dose. There’s a big trial that’s underway in Australia at the moment which has been organised by the Walter and Eliza Hall Institute for Medical Research. That’s testing this quite controversial drug that Trump, amongst others, have advocated, hydroxychloroquine. There’s probably pretty good evidence now coming in that hydroxychloroquine is not a very good treatment for coronavirus, but it may be – and the trial will tell us – whether it could be used as a prophylaxis.

The problem with any prophylactic drugs, drugs that you would take to avoid getting sick, is that all drugs have side effects. If you’re going to give drugs to, let’s say your whole population, to try and prevent them from becoming unwell, then there are going to be a number of unwanted adverse events from all of those otherwise well people taking drugs.

ANDI HORVATH
Okay so gentleman, I put it to you then, why drugs and why not then the efforts into the vaccine or will it be a combination of both? Sorry, that’s a double-barrelled question, but I’m essentially saying, why drugs then?

STUART RALPH
I think that most of the diseases in the world that we are pretty good at handling are diseases where we have both options, where we prevent them where we can but then once you do get infections that you’ve got an option for treatment. We don’t see this as an either/or option. We think that it would be great to have a vaccine and it would be great to have treatments as well for those people who do become unwell. The other thing is that it really doesn’t look like we’re going to be able to have a vaccine that is widely usable until at least the end of this year, maybe quite a lot later than that. It would be good if we could find a drug that we know is safe to use in other circumstances and repurpose that drug for treating COVID-19. In that case, we would at least have one option to minimise death and illnesses until a vaccine becomes available.

CRAIG MORTON
Yeah. So, in the case of COVID-19, remdesivir and dexamethasone have both been shown to have significant impacts on medical outcomes. So remdesivir is a drug that targets viral replication. It wasn’t designed for COVID-19 but appears to work on COVID-19. Dexamethasone is an immune system modulator that actually turns your immune system down slightly, and in the very sick patients that seems to be a clinically extremely useful thing to do. So, by repurposing existing drugs, you can rapidly get from having no possible treatment to having at least some way of mitigating the infection and improving the outcome of patients. Whereas developing the vaccine is clearly going to take months to years from now.

ANDI HORVATH

Can I get you both to comment on the complexities of drug design and even vaccines? I mean, it involves getting together with large pharmaceuticals, and also you need money to develop drugs and vaccines. Give us a little bit of context on how you manage that.

CRAIG MORTON
Andi, you’re right that there’s significant costs involved. A lot of what we do at a university level is focused on the initial does this compound have any chance of working against the virus. So, we’re looking at isolated enzymes or proteins that the virus makes, looking to see how they might interact with known drugs or new compounds that might be out there. But that’s only a very early stage in the drug development process. Now, if you’re able to find, in this search for a compound that might work on the virus, a drug that’s already approved for use in people, that’s the ideal situation. That drug can then be tested quite quickly because we already know how it behaves in people, what doses can be tolerated, all those sorts of things.

If you’re starting from scratch, saying I need to find a brand new compound, traditionally it takes three to five years of lab research before you get to a point of understanding the chemistry of the potential drugs before you’d start testing them in people. That process of testing in people takes, normally, five to 10 years and costs hundreds of millions of dollars. The clinical trial stage is very expensive and requires an enormous amount of investment. That’s where partnering with large pharmaceutical companies is almost inevitable. The ability to absorb those costs upfront, with a known chance of failure, not every drug that goes into clinical trials makes it to the market, makes money to pay back the costs to the investors, to the government who may have helped fund it. It’s a very, very significant investment in time and expense to go from an idea of a drug against a particular virus to a tube of chemicals that can be given to a patient on the market.

STUART RALPH
I would say the other side of that, the kind of dirty secret of drug discovery is that because that drug discovery is so expensive, it really does mean that we, these days, only have very good drug discovery against diseases where it would be lucrative to treat that disease. Unfortunately, there are lots of infectious diseases – and rotavirus that I mentioned before, is one of those that really disproportionately affect the poorest people in the world. That means that there’s not much of a profit motive for developing drugs, including antivirals, against those. That really has meant that they’ve been neglected to a great extent over the last 30 years, which leaves us in a terrible place for treating some of these really awful international diseases.

CRAIG MORTON

I will point out that there are government organisations around the world that specifically fund these less well-addressed diseases, purely because of the impact they have on the human population. So while, yes, the big pharmaceutical companies might not make it their priority to be working on those diseases, they will have programs in those areas that are funded by government organisations or non-government organisations, that are raising funds to work specifically on poorly-targeted tropical diseases, for example.

ANDI HORVATH
Craig, can I ask you, what’s changed in drug design since you’ve entered this industry?

CRAIG MORTON

I think the biggest thing that’s changed for me is the speed with which we can do things. For example, one of the viruses I worked on for many years is a virus called respiratory syncytial virus. It causes cold-like symptoms. It’s probably the first disease almost every child gets; most children have been infected with it before the age of two. In most children, it causes cold-like symptoms. They get better, and a lot of children, about 10 per cent however, they get quite a severe infection and require hospitalisation. Now, I worked on that for 10, 11 years, that particular virus. We were guessing a lot of the time the details of what we were working on because we didn’t have the detailed three-dimensional structures of the proteins that we need because the techniques 15 - 20 years ago when I started working on it, weren’t up to it.



When SARS was identified towards the end of last year, SARS-2, the virus that causes COVID-19, within a few months there were three-dimensional structures – these detailed, beautiful structures of the spike protein, of the proteases, of the replicating enzymes. The speed with which you can take the knowledge of what the genome of the virus is and generate the structural information that I need for my work has gone from being years and years of painstaking effort to a rapid turnaround where one to two months from having the sequence to having structures, and that’s made an enormous difference to what can be done and how it can be done.

ANDI HORVATH
That’s good to hear actually. Stuart?



STUART RALPH

I think something that’s striking about this pandemic is the – even though it’s a terrible, terrible pandemic, we’re kind of lucky that it hit now rather than 30 years ago. A lot of the technologies that we now have in place mean that we can do things that we absolutely couldn’t have imagined 30 years ago. The technologies that we have for diagnosis, for detecting the genome of the virus or, potentially in months to come, detecting the antibodies in humans that arise to the virus; the technologies behind those things have really come forward in leaps and bounds. This other concept that we’re hearing through the media of sequencing the genome of viruses in different people to be able to trace where the virus has been moving also would have seemed absolutely science fiction to us even 10 years ago.

So, the fantastic advances we’ve had in the basic technologies like genome sequencing or expressing proteins or electron microscopy, some of these advances really mean that we are much better equipped for tracing, for diagnosis, for planning, for modelling, and then hopefully for coming up with better vaccines and for better drugs. Some of the technologies that have been discussed for making new vaccines include really quite science fiction things like making recombinant viruses by injecting RNA into people, synthesising new proteins. These are approaches that are really reliant on modern molecular sciences. We’re lucky that we do now at least have approaches that we can use to diagnose and trace and model these things and to treat them.

ANDI HORVATH

I guess like most journalists, we’re keen to ask, are we there yet? Are we there yet or can you see the end where you’re standing?



STUART RALPH

I think the answer to that is that we are certainly not there yet. We really don’t know whether any of the vaccines that are in the pipeline at the moment are going to provide adequate protection that we can roll them out as a way of solving this problem. In terms of drugs, we’ve got a couple of options now that give some degree of protection to people who are already very unwell, but we really don’t have a magic bullet. What we’d really like is a drug that would come along, that we could discover, where anyone who had COVID-19 would take that drug, and it would give them at least a 90 per cent chance of resolving those symptoms quicker. But that’s not the case. The two drugs that are potentially being used in Australia, remdesivir and dexamethasone, they’re drugs that give you a small, maybe 30 per cent, protection either from death or from severe illness, depending on circumstances. But that’s not really enough at all. 

That really still means that there will be people getting very unwell, people dying, and people transmitting the virus. We’re not at a situation where we have the answer, where we have a drug that can really adequately deal with this problem, so we need to keep on looking.

CRAIG MORTON
Yes, I would agree with Stuart completely. At the moment we know a lot more than we did six months ago, but we’re not able to say when we’ll have drugs that work, when we’ll have a vaccine that is clinically effective. The latest data on some of the vaccines is very promising. They’re showing a good safety profile, which means that they don’t make the patients who’ve received the vaccine sick and shown that they are producing neutralising antibodies in those patients, which is what you want a vaccine to do. But we’ve got no idea whether that neutralising antibody level is sufficient to protect someone from coronavirus infection. With the drugs, we’re working on it. As Stuart says, we’ve got ones that have been approved for treating very, very sick people to improve their chances of recovery. Drugs for the man in the street to make sure that they don’t get sick? I think they’re still a long way off.



ANDI HORVATH
What would you like us to think about next time we’re looking at a packet of drugs or hearing about drug design in the media? What is it that you’d like us to understand?

STUART RALPH
I think people already have a pretty good understanding, in some countries, that there are differences between antiviral drugs and antibacterial drugs, which we often call antibiotics. I think something that’s important to remember is just how difficult it is to target viruses, and how difficult it is to make drugs against viruses. The other thing that I think is worth remembering is how reliant we are on drugs to treat infectious diseases. That’s something that is being threatened at the moment in a number of areas, both in viruses, bacteria, and in parasites, where the infectious agents are becoming resistant to the drugs that we’re using. I think this is a really worrying development that’s occurring in lots of areas, in agriculture as well as in medicine. 

Think about the terrible state that we’re in at the moment with no drug to treat COVID-19. Imagine if that were also the scenario for treating bacteria and parasites. What a dreadful state we’d be in. It really does reinforce for us the absolute crucial role that anti-infective drugs play in society. The really important, sort of worrying, problem that we have of any microbial resistance, which is developing in a number of areas, that’s probably a conversation for another day, but it’s a [sombering] glimpse of a future world where we don’t have good drugs to treat infectious diseases.



ANDI HORVATH

Very true, Stuart. Craig?

CRAIG MORTON

I’d first reinforce Stuart’s comments on drug-resistant microbial pathogens. It’s a huge, growing problem that needs further investment as we go forward. But the other thing I think people need to consider when they look at the packet of pills is the amount of effort and work that’s gone into producing those pills. There is lots of discussion about how drug companies are evil money-making creatures who squeeze us all for cash. The research and development that goes into coming up with a new drug is very, very expensive, hundreds of millions of dollars. That money has to come from somewhere. 

The pharmaceutical companies spend vast majority of that development cost from money they raise themselves. A lot of it comes from government as well, but the majority comes from the pharmaceutical companies. The companies aren’t evil monsters. They’re doing their best to come up with products that are safe and effective for human use. I think take a slightly friendlier view of drug companies when you realise that we are reliant on a lot of the produce that comes from these companies, as Stuart said, in all different aspects of health within our society.

ANDI HORVATH

Doctor Craig Morton and Associate Professor Stuart Ralph, thank you very much.

CRAIG MORTON

Thanks a lot, Andi.

STUART RALPH
Thank you very much, Andi, for your time.

CHRIS HATZIS
Thank you to Associate Professor Stuart Ralph, Acting Head of the Department of Biochemistry and Molecular Biology in the School of Biomedical Sciences. And Dr Craig Morton, Departmental Senior Research Fellow based at the Bio21 Molecular Science & Biotechnology Institute, both at the University of Melbourne. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on July 21, 2020. You’ll find a full transcript on the Pursuit website. Production, audio engineering and editing by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2020, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis. Join us again next time for another Eavesdrop on Experts.