Experts Develop Computer Modeling To Speed-up The Development Of Antiviral Drugs


Effective drugs against viral diseases like COVID-19 are urgently needed now and in the future. All the more so as the emergence of mutant viruses and emerging viruses could push vaccines to their limits. DZIF scientist Andreas Dräger is working at the University of Tübingen on a computer-based process that can speed up the time-consuming identification and development of antiviral agents. Using a novel analysis technique that can be transferred to any virus and host cell, the scientists were able to create a model and thus detect further points of attack for SARS-CoV-2.

“Efficient pandemic prevention requires new, broadly effective antiviral drugs to which the viruses cannot quickly develop resistance,” explains Andreas Dräger, junior professor at the University of Tübingen and member of the Tübingen Cluster of Excellence “Control of Microorganisms to Fight Infections – CMFI”. “However, the development of active ingredients requires a great deal of valuable time, which is of the essence in an emergency.” Dräger wants to use its computer modeling to remedy the situation.

As early as 2021, the Tübingen working group was able to identify a human enzyme in the model – guanylate kinase 1 – that is essential for virus replication and can be switched off without damaging the cell. Now the bioinformatician was able to develop another model with his teammates to test the significance of their goals. “Thanks to an improved analysis technique, we can now specifically model viral infection in many different tissue types,” explains Nantia Leonidou, the first author of the current study.

Observing metabolism after viral infection in a model
The Tübingen-based integrated systems biology model simulates an infection with SARS-CoV-2 in bronchial epithelial cells and then identifies host-based metabolic pathways that can be inhibited to suppress viral replication. “If you know the composition of a virus, you can run through different scenarios and see how the biochemical reactions in the host cells change during a virus infection,” says Dräger. The team developed high-quality software to simulate a cell-type-specific infection.

New targets identified
Using the model for another cell type, the research group was able to confirm the previously identified target molecule, guanylate kinase, and discover other new targets with remarkable antiviral effects. The most promising new hit was CTP synthase 1, an enzyme whose inhibition also reduced viral growth by 62 percent without affecting cell maintenance in the human host. Both target molecules are closely linked to the structure of the genetic material, which requires the same building blocks in both the virus and the host.

Andreas Dräger’s team assumes that these results represent an important basis for the faster development of viral inhibitors. “Our models could represent a paradigm shift in drug development and accelerate the preclinical phase,” emphasizes Nantia Leonidou, adding: “The methods can be fully transferred to any virus and host cell type and can also be used commercially.”

Dräger’s group now wants to apply their methods to other viruses. The first inhibitors for the enzymes they have found are to be tested in animal models for safety, toxicity and effectiveness.