It was September 2019 and I was speaking at an international conference in Wuhan, China. On stage I explained that the world was not prepared for the next pandemic; It was the classic lecture he would give on some of the virus families that pose a risk. One of the ones I mentioned that day was coronaviruses. Thinking back, I would never have imagined that just a few months later a coronavirus detected in Wuhan would be at the epicenter of a pandemic . But imagine if at the time SARS-CoV-2, the virus that causes Covid-19, was first detected, doctors in China could have given their patients some powerful and comprehensive antiviral drugs that work against coronaviruses. . Doctors and nurses could also have protected themselves. Had it been caught early enough and with quarantine measures, it could have slowed or even stopped the spread of the virus.
We can never know for sure, but the current situation could have been very different. And this is what motivates me every morning. If we can find drugs that act against viruses before they become a problem, we can turn global wildfires like Covid-19 into small bonfires. Here at the Rega Institute at KU Leuven in Belgium, this is exactly what we are trying to do. We are looking for molecules that can form the basis of powerful antiviral drugs that can be administered to Covid-19 patients. What we are looking for are compounds that interact with the virus and prevent it from replicating.
But finding the right molecules is like looking for a needle in a haystack. So we are involved in two complementary approaches to doing this. One is the EXSCALATE4CoV project, which uses artificial intelligence and high-level supercomputing to predict which compounds might block the virus’s replication cycle based on what we know about the structure of SARS-CoV-2 and its interaction with proteins outside. of the cell. Our EXSCALATE4CoV partners use the largest European supercomputers to search a massive chemical library by running millions of simulations every second to see if they can bind to a particular target site on the virus and block its replication.
When you identify a compound that might work, chemists make it and send it to us (to the Rega Institute) for testing against the infectious virus. This work is done in a fully automated lab that we have built called Caps-It. We are also using Caps-It to follow a more traditional approach to drug discovery in another project called SCORE. For this, what is called blind detection is used, in which the antiviral activity of thousands of molecules is evaluated against the virus that grows in the cells. You need enough capacity to test so many molecules against this highly infectious virus in living cells. Caps-It has allowed us to be one of the few laboratories that are equipped to safely test large numbers of compounds against live viruses such as SARS-CoV-2.
Biosafety Laboratory
Caps-It is a complete test lab sealed within what is effectively a box. Everything is done by robotics: manipulating the pathogen, adding reagents, incubating, testing and deactivating the infectious material, so no human needs to come into contact with the virus or enter. My team can even operate the system while sitting at home at night via webcams if necessary . In a high-end walk-in biosafety laboratory, rooms have to be pressurized, expensive to operate, and take up a lot of space. Technicians must wear protective suits and can only work indoors for a few hours. Caps-It can work 24 hours a day, seven days a week.
It was designed by one of my senior team members a few years ago, who came up with the idea and worked with specialized engineers to build and install it. What we had in mind was that in a pandemic situation we would need to test compounds day and night, but we didn’t want lab technicians to do that with a highly pathogenic, dangerous virus, so let’s fully automate it. Once it’s built, we gradually prepare it over the first few years, first virus-free and then low-pathogenic virus. So just when we were ready to accept highly pathogenic viruses, boom: it’s 2020 and Covid-19 is here. We were ready just in time with the installation at a really crucial point to run a large number of compound tests against the virus.
The system can test thousands of different chemicals at the same time against a virus. The system has room to incubate up to 480 test plates at a time, each with 96 or 384 wells (small holes in which virus, test compounds, and cells can be placed).
Chance
So far we have performed close to 2 million tests on compounds in cell-based systems, and every 30-40,000 compounds we test, on average, we find what we call an impact compound, a molecule that could block virus replication. , just by chance . But that’s just a starting point. Once we have detected an interesting new target, we have to work with chemists to optimize it and increase its potency and selectivity. Next, we need to test it on animals, and we’ve developed a hamster SARS-CoV-2 infection model that allows us to do that.
So I would say that these two approaches, AI and blind detection, go hand in hand. We have already identified some compounds that could become potential drug treatments for Covid-19 and they show promise in hamster models. Some are experimental antiviral drugs or existing drugs against other things. We were also able to show that hydroxychloroquine, which some people claimed could treat Covid-19, had no activity.
The AI approach is a powerful technology and, together with blind detection, it helps us identify the Achilles heel of the virus. Speed things up.
Paramixovirus
This (approach) will not only be important in the current pandemic, but also to address or prevent future pandemics. There are a number of virus families from which potentially highly contagious and dangerous viruses can arise. One of those families is the paramyxoviruses, which includes measles. It took just under 12 months to create highly effective Covid-19 vaccines, which is staggering. But Covid-19 has a basic reproduction number (R0 – the number of people to whom an infection can be spread from one case) of 2-3, while something like measles has an R0 of around 15. If you have With a virus like that spreading, having to wait 12 months for a vaccine will be too late. We did some modeling with colleagues here in Belgium that showed that even non-high potency drugs against Covid-19 would be enough to help mitigate local outbreaks.
That is why we need antiviral drugs that can slow the spread of infected people and reduce the severity of the disease they contract. We spend trillions of dollars on weapons and military spending, so surely we should also be arming ourselves against the next pandemic. We need a global insurance policy for the 7.7 billion people on the planet. That is my mission.
Original article
This article was originally published in Horizon, the EU Research and Innovation Magazine
