A drug lead molecule studied by Viikki Biochemists may help in fight against COVID-19

Since 2014, Tenure Track Group Leader Ville Paavilainen’s laboratory has been investigating a molecule, which now shows promise in targeting the new coronavirus. In the best-case scenario, this work could lead to development of a new drug to help alleviate symptoms and prevent progression of COVID-19.

Biochemist and Academy of Finland fellow Ville Paavilainen was surprised to discover in his research a firm link with the fight against the coronavirus. Paavilainen’s laboratory conducts basic research focused on the protein homeostasis of cells and proteins secreted by cells.

“We are investigating a range of small molecules that are disturbing this homeostasis to learn more about cellular processes. To us, they serve as a tool, but the same molecules can also work as precursors for drugs.”

The secretory pathway proteins Paavilainen studies have a key role in many cancer types as well as in diseases where the structural problems found in the proteins produced, known as misfolding, have an effect on disease progression. Among other disorders, misfolding is characteristic of cystic fibrosis.

“We may discover precursors of drugs suited to treating the very same diseases.”

Aiming to prevent viral multiplication

Coronavirus-related news have frequently mentioned a so-called protein grappling hook, found on the surface of the coronavirus and used by the virus to attach itself to cells in the human respiratory tract. However, attaching and entering are only the first step on the path to success for the virus.

Once inside the cell, the pathogen needs to multiply, and most viral proteins needed for replication are produced in a certain organelle of the human cell: the endoplasmic reticulum in the cell membrane. The assistance provided by the protein machinery of the endoplasmic reticulum is vital to the virus.

It is precisely this machinery and the molecules inhibiting its function that Paavilainen’s laboratory has been focusing on.

“We have studied a molecule that inhibits influenza and Zika viruses, which is also a promising drug candidate for certain cancer therapies. Now, all of a sudden, a site of action was identified for this same small molecule in the coronavirus. In other words, we have been tinkering with a potential coronavirus drug precursor in our laboratory for a long time.”

A drug suited to treatment and prevention

To carry out additional investigations, Paavilainen has applied for special funding targeted at COVID-19 research from the Academy of Finland. The work is based on structural biology data continuously produced by Paavilainen’s laboratory in cooperation with its partners.

While doing this, they are also looking in more detail into how molecules disruptive to viruses affect the coronavirus.

“We are experimenting in a cell culture model with inhibitors on virus specimens extracted from patients. In this, we are collaborating with Professor Olli Vapalahti’s laboratory.”

The next step is animal testing on mice.

“All over the world, people are feverishly working to deploy a mouse model for COVID-19. We too would be more than happy to test the efficacy of our most promising compounds.”

The goal is to discover a drug that could be used broadly in different stages of treatment.

“As a biochemist, I believe this drug type could be used to treat patients in all disease stages where viral multiplication and the resulting cell destruction aggravate the disease. Based on what I know, this already begins before symptoms start to show and continues almost until recovery.”

In the best-case scenario, the drugs would also benefit healthy individuals.

“They could be used to inhibit the ability of the virus to infect and replicate among the asymptomatic population.”

Cancer or antiviral drugs?

This is not the first time drug developers and businesses have been interested in Paavilainen’s findings. In San Francisco, a company called Kezar Life Sciences is founded on work to which Paavilainen contributed when he was working as a postdoctoral researcher in California.

“The information gained from the molecules I studied constitute the foundations of the company. Now that my research group is collaborating with them and other companies, we are able to simultaneously produce open-access data for the scientific community.”

Typically, the business idea behind companies like Kezar is to develop molecules suited to cancer therapies.

“Antiviral drugs have not been considered as attractive commercially, but the coronavirus may change that.”

Paavilainen describes his research approach as discovery science.

“Our aim is to produce fundamentally novel research findings from the perspective of science, but ones that can be applied in practice.”

Unforeseen benefits of basic research

Paavilainen’s workplace is located in a dedicated laboratory on Viikki Campus at the Institute of Biotechnology, part of the University of Helsinki’s Helsinki Institute of Life Science (HiLIFE). In recent weeks, he has also been serving as a member of a COVID-19 research group that was quickly assembled from among the University community.

Knowledge of epidemics and viruses was already available in a number of research groups active in the faculties of the University. Alongside Paavilainen, the extensive group of specialists includes Professor Olli Vapalahti, who specialises in zoonotic diseases; Tarja Sironen, associate professor of emerging infectious diseases; and Professor Mark Daly, a specialist in genetics.

“Had we been forced to begin our work without previously acquired knowledge on other coronaviruses at the beginning of the outbreak, we would be years behind our current situation. You can never know in advance which discovery will turn out to be useful in the end,” Paavilainen points out.

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