In the frame of MIMS highlights World Antimicrobial Awareness Week 2021
Text written by Nóra Lehotai and Niklas Arnberg.
Niklas Arnberg is Professor of virology at the Department of Clinical Microbiology at Umeå University, Senior PI at MIMS and Chairman of the Virus and Pandemic Foundation (Pandemifonden). He is enthusiastic about the unique research environment in Umeå, a special island within academia, created by researchers from MIMS, UCMR, all life science departments at Umeå University, Region Västerbotten and Biobank Norr. He would like to encourage everyone to talk to each other, collaborate and discover foremost new antivirals together.
Picture: Niklas Arnberg. Credit: Mattias Petterson.
Awareness about antivirals
All known vaccines that we have right now against all pathogens, are working specifically against a certain pathogen.
Niklas Arnberg explains that
“the available SARS-CoV-2 vaccines, both mRNA- and vector based, prevent, and protect against SARS-CoV-2 and COVID-19. However, the next pandemic caused by a currently unknown coronavirus present in bats, could be called SARS-CoV-3. We have hundreds or thousands of different coronaviruses in bats and other animals, and we do not know which one will cross the species barrier again and cause another pandemic. The current SARS-CoV-2 vaccines will not work against that kind of coronavirus. However, the currently developed antiviral drugs against SARS-CoV-2 are likely to be effective against other SARS-CoV infections, including a SARS-CoV-3. This is the kind of proactive, long-term work that we think is needed today in order to better manage future pandemics. Me and some of my colleagues, we have talked about the need of antiviral drugs before the SARS-CoV-2 pandemic, we are talking about it during the pandemic, and we will probably have to talk about it after the pandemic also.”
Advancements in SARS-CoV-2 antivirals
The good news : at least two antiviral drug candidates coming up against SARS-CoV-2 and treating COVID-19. One of them has just been approved in the UK, called molnupiravir, developed by Merck. This seems to be really efficient, reducing the risk of dying in COVID with 50%, probably more if it is given early. This is a typical nucleotide analogue, similar to antiviral drugs that we have against HIV, herpes- and hepatitis viruses. The second one was developed by Pfizer, which most people have heard about by now with respect of the COVID-19 vaccine. They have now completed the phase II/III clinical studies where they showed that their antiviral candidate against coronavirus is also very efficient. The Pfizer-developed drug is a protease inhibitor, targeting the protease of the virus.
Why we need antivirals and more of them
The coronavirus family is just one out of more than 20 different virus families. Some of them contain several hundreds of different virus types, causing disease in humans and we lack antiviral drugs against almost all of them. It is important to talk about this and address this gap.
“If we get more drugs against these viruses, it is not only that we will be better prepared against future pandemics, but we will also have much better tools to treat the other virus-caused infections and diseases that we cannot treat today”-continues Niklas.
Just before the onset of this pandemic, Södersjukhuset in Stockholm was put into emergency because of the winter vomiting disease (vinterkräksjuka in Swedish, caused by norovirus). The Sahlgrenska Institute was put into emergency a few years ago because of a measles outbreak, which is preventable by vaccine, but to treat the infection, we don’t have antiviral drugs available. Now, the RS virus is causing serious problems in health care, threatening the lives of babies and small children. These outbreaks put extreme burdens on hospitals not only because of the number of seriously ill patients but also stealing resources from other type of health care.”
We do not have any drugs against any of these relatively common viruses. In the picornaviridae virus family for example, we have hundreds of viruses, including poliovirus 1, 2, and 3 that we can prevent with vaccines but the enteroviruses, which belong to the same family, have polio virus-like properties and if enteroviruses mutate to become something like a poliovirus type 4, the regular poliovirus vaccines will not work, and then we would be in serious trouble.
“If there would be more antiviral drugs against more viruses, such as enteroviruses, we would not only be much better prepared against virus-caused outbreaks and pandemics, but we would also relieve a substantial burden from hospitals, saving more lives and transfer resources for example, to mental health.”
Antiviral resistance in viruses
Viruses mutate and they can also develop resistance but not with the same mechanisms as bacteria. Bacteria can share resistant genes between each other even if they are not very related.
“Viruses, however, do not do that. Says Prof. Arnberg. Their resistance against antiviral drugs simply develops through point mutations occurring when the virus duplicates its genome in infected cells.”
Bacteria can also develop resistance through mutations. DNA viruses mutate slow, comparable with bacteria, but RNA viruses change a lot.
“To illustrate this, let’s take HIV (human immunodeficiency virus), a retrovirus, causing AIDS. The enzyme responsible for making copies of the virus, makes lots of mistakes. When the first antiviral drug was developed against HIV and given to infected patients, one noted that the viral load decreased quite a lot just in days after giving the drug, but few months later, the viral load increased again. This happened because of the “mistakes” the enzyme made while copying the virus, creating resistance against the antiviral.”
Nowadays, this problem is solved by giving combination therapies, giving not only one but two or even three antivirals at the same time, so it will be too difficult, almost impossible for the virus to mutate away from all drugs, resulting in low viral load for a long time.
“The reason why we cannot cure HIV infection is a special enzyme, called integrase. This integrates the viral DNA into our chromosomes where it lies silent thus, we are not able to kill the infected cells.”
The number of viruses that we can cure, is very few, less than ten. Hepatitis C is one of them and unlike HIV, cannot integrate its genome in our chromosomes. With combination therapies of effective drugs, millions of people can now be cured from hepatitis C infection and saved from dying in liver cancer.
“You see, the big, current problem with antivirals is not resistance, which is present at a low level of course, but rather the lack of antivirals.”
Picture: Vaccination. Credit: Mostphotos.
It is challenging to find new antivirals
Niklas Arnberg points out three reasons. One reason is that all viruses are intracellular parasites meaning that they go into our cells, where they replicate. It is only within our cells that they expose most of their potential targets that we can aim at with antiviral drugs. These targets can be enzymes such as polymerases and proteases.
“The antivirals we develop, must enter our cells, which is challenging already because of the risks of side effects, but they also have to remain effective there and specific after getting inside the cells. Another reason is that compared to bacteria, viruses are very small and there are not that many targets that we can aim at.”
The last reason is that virology is a relatively young research area. Modern virology started some fifty or hundred years after other areas in microbiology, because there were no good model systems to study viruses.
“In the 50’s, we got access to cancer cells which are the model systems that we use to study virus infections and to identify targets for antiviral drugs. Because of its young age, there are still not that many people who work with it. I would like to have more colleagues and “competitors” in this field. If so, that would lead to faster development of more and better antiviral drugs. “
Viruses with surface structures: friend or enemy
Our immune system develops antivirals in the form of antibodies that behave like antivirals: they neutralize viruses that are released from infected cells.
“I think we can, and we probably should look more into these viral surface structures and learn from our immune system. Targeting these parts of the virus when they are in their extracellular phase, thus more accessible, could be an efficient way to kill them and treat virus-caused infections.”
A German researcher, Stephan Urban, has developed peptide based antiviral drugs against hepatitis D and B viruses, causing co-infection, that target certain proteins on these viruses, proteins like the spike protein on the coronavirus*. This drug has been approved in 2020 by the European Medicines Agency (EMA). *https://www.dzif.de/en/first-drug-hepatitis-d-has-been-approved-european-commission
“It is also something that I have done research on for quite some time. Together with Mikael Elofsson (Dean Faculty of Science and Technology, Professor at Dept. Of Chemistry), we targeted adenovirus fibers which bind to glycans on the surface of corneal cells. Although the project did not result in the end in commercializing our discovery, we learned a lot on this journey and we now use the technologies, knowledge, and some of the compounds that we developed together against other viruses that also use glycans as receptors.”
Future: helping our immune system and diagnostics
Previously, over the years, one has been given interferon to people being infected with e.g. hepatitis viruses. Interferon works as both immunomodulatory and antiviral drug, activating more than 300 different antiviral genes and all these different genes target different types of viruses caused infections and by specific mechanisms.
“If or when we get more knowledge about what exactly these 300 different genes do, it may be possible to activate specific pathways targeting specific viruses, without causing the typical side effects of immune response such as headache, tiredness, fever, and not being able to work.”
RNA-interference is part of our innate immunity, representing one way of targeting virus caused infections. We are activating our immune system also with the different types of vaccines, giving us a protection against developing illness.
“We have our mucosal tissue, serving as a barrier against viruses, with the mucus containing lot of glycans, Niklas continues. These are the glycans that we are now mimicking with our drugs. These glycans are present on our cells and the aim is to design equivalent glycans, recognized by virus receptors. We think that if we can improve this natural barrier by adding our designed compounds, we could complement our immune system to fight off viral infections. What could be also attractive with this approach is that it can be given as a nose spray or an inhalation device. These kinds of compounds are not classified as drugs, and one could buy it over the counter without having a prescription.”
Picture: Bacteria in the intestine. Credit: Mostphotos.
Connecting to this, Niklas Arnberg thinks that it is super interesting that the recent developments in molecular diagnostics will allow us to do quick PCR tests at primary healthcare centers.
“If I become ill, I will be able to go to the primary healthcare center, give them a sample and then within an hour or two, they can tell me what kind of infection I have. Then they can advise me to buy for example an over-the-counter medical device, working against that specific type of virus infection I got diagnosed with. I will know whether I need to stay at home to avoid infecting others and when I can be back at work or school. With such a strategy, we can prevent transmission within the society, which is of utmost importance when it comes to the elderly and other risk groups.”