Intensive hunt for drugs to fight COVID-19

13 May 2020

Åke Lundkvist, professor of virology and Johan Lennerstrand, docent in clinical microbiology both belong to the research group Zoonosis Science Center (ZSC) at BMC.

The entire world is currently waiting for a vaccine against COVID-19. Intensive research is ongoing to develop useful drugs against the novel coronavirus SARS-CoV-2. At Uppsala Biomedical Centre (BMC), substances are being tested that attack the same type of enzyme as drugs against HIV and hepatitis C.

“We want to develop antiviral drugs that focus on different targets in the virus. We will need several effective drugs, and they should preferably be administered easily in tablet form, not intravenously like the drug Remdesivir,” says Johan Lennerstrand, docent in clinical microbiology at the Department of Medical Sciences.

Johan Lennerstrand, docent in clinical microbiology
at the Department of Medical Sciences.

His research team is focusing on producing substances that can inhibit a unique enzyme, the “main protease”, which is found in the virus but not in human cells.

“Such protease inhibitors have successfully been developed to treat HIV and hepatitis C in the past,” says Lennerstrand, who has been researching drugs for HIV for twenty years and about drugs for hepatitis C for the past ten years.

With the help of research colleagues in Oxford and at Karolinska Institutet (KI), they have gained access to the SARS-CoV-2 protease in its pure form. Their research is initially being conducted at SciLifeLab’s Drug Discovery and Development platform, where they can utilize computer-based virtual screening combined with SciLifeLab’s extremely large substance library.

“These substances are DNA-labelled and act like small Lego pieces. Binding two or three Lego pieces can result in billions of different variations, depending on the size of the library of substances. This is a unique tool, usually only available at large pharmaceutical companies. But now we have access to it, thanks to SciLifeLab.”

Starting point for new drugs

Between the enzyme and the different substances, he expects that they will find several interesting candidates. Once identified, they will continue work with these candidates together with Anja Sandström, a researcher at the Department of Medicinal Chemistry, who has extensive experience developing protease inhibitors against hepatitis C and HIV.

“When we have obtained the first candidates with drug chemistry synthesis, we will test to ensure they are not toxic, partly in enzymatic tests and partly in the biosafety level 3 laboratory here at Zoonosis Science Center. We may be able to contribute a piece of the puzzle together with many other researchers who are doing the same thing internationally. We are developing the starting points from which drugs can be developed.”

In addition to testing that the substances work in cell cultures, it is necessary to check that the drug is absorbed and transported in the body properly and that it is not harmful to the patient. If necessary, small changes need to be made, and this is also something that SciLifeLab can help with, since its mission is to work with both pharmaceutical companies and academic groups to develop potential drugs.

“With some luck, we hope to quickly find promising substances with direct effect on SARS-CoV-2 that can begin clinical studies within two years. Real muscles are needed to do the clinical studies, and that’s the job of pharmaceutical companies. Normally this would take at least five years, but the need is so urgent that an antiviral drug will be created in record time. Several drugs are also needed that attack different targets in the virus.”

Tests existing drugs

They are already testing existing drugs that could treat the novel coronavirus.

“We will also test previous advanced protease inhibitors, such as what the drug company Medivir developed for other viral infections but chose not to proceed with clinical studies. We will study them both enzymatically and in cell culture. We also use computer simulations and have access to enormously powerful computer software through Uppmax and SciLifeLab,” says Lennerstrand.

Zoonosis Science Center (ZSC) at BMC serves as the actual meeting place for the research. They are focusing heavily on research about the corona pandemic. In addition to drugs, they develop tests to investigate the spread of infection and immunity in Sweden.

“Once we realized that the virus had become epidemic in Sweden, that is, that it is something that we will have to deal with for some time, we gradually refocused our research,” says Åke Lundkvist, professor of virology who leads ZSC.

Many different types of expertise

This was facilitated by research funding organisations both in Sweden and the EU approving the use of grants for other projects for research on the novel coronavirus.

Åke Lundkvist, professor of virology, who leads
Zoonosis Science Center.

ZSC began in autumn 2014 and the following year the biosafety level 3 laboratory at BMC opened. This was in connection with Åke Lundkvist becoming professor at Uppsala University. Lundkvist had previously worked at KI and the Swedish Institute of Infectious Diseases, which later became the Public Health Agency of Sweden.

Together with Björn Olsen, professor of infectious medicine, he has built up a research team with a core of 15–20 people with many different types of expertise.

“In our team, we have virologists, bacteriologists, entomologists, drug experts, veterinarians and medical researchers. What is amazing is that we now have a collection of people in our Zoonosis Lab that is perfect for researching the SARS-CoV-2 virus,” says Lundkvist.

The research mainly focuses on finding and developing tests that detect antibodies to the virus. These are both rapid tests and more advanced tests, and the goal is to create a more realistic picture of the extent of the spread of the virus in Sweden.

Fewer than believed have antibodies

Recently, tests were conducted on 454 individuals in Stockholm. These tests showed that only 7.5 per cent had antibodies, which differed significantly from the calculations made by experts at the Public Health Agency.

“We will wait to say more about how immunity is progressing until we have conducted another round of tests in late May.”

Many people are hoping for flock immunity, but Åke Lundkvist finds it difficult to know what that means in this case.

“No one knows how the spread of the virus will develop and what it takes for flock immunity to kick in. We can only speculate.”

We may have to wait for a vaccine and effective drugs before society can return to normal. One thing is certain: researchers around the world are working hard to solve this challenge.