A new method to better understand how drugs work
According to a study published in Nature Communications, researchers at the Department of Laboratory Medicine, Karolinska Institutet have made a significant leap in drug discovery and development with a new method called CeTEAM. This approach connects how drugs bind to their targets inside cells with the effects they produce, offering a clearer understanding of how a drug works.
According to the researchers, CeTEAM could become a vital tool that could transform how new therapies are developed and evaluated, ultimately improving treatments for patients.
“CeTEAM allows us to see how drugs interact with their targets in live cells, which is crucial for understanding their effects,” says Nicholas Valerie, Assistant Professor at the Department of Laboratory Medicine and the study’s lead author. "This method demonstrates that variants of known therapeutic targets, such as the DNA repair protein PARP1, can be useful for understanding how potential drugs act, including intended effects and unintended side effects. For instance, when some drugs bind to PARP1, they can sometimes trap it on DNA, thereby affecting its function and the therapeutic response in patients."
More efficient screening of drugs in cells and preclinical models
Traditional methods have struggled to link target binding (also called drug-target engagement) to cellular responses of a given drug. Nicholas explains, “Our new method provides insights that might otherwise be difficult to obtain, helping us identify which drugs might be most beneficial for patients. The study also reveals that protein variants that can be used to visualise drug interactions may be more common than previously thought, expanding the potential applications of CeTEAM.”
One of the key advantages of CeTEAM is its ability to measure a drug interacting with its protein target without changing the cellular environment. This means researchers can observe how cells respond to drugs over time and gain insights to their mechanism-of-action.
Mikael Altun, Associate Professor at the Department of Laboratory Medicine and a senior author of the study, continues, “Because of how our approach works, we can screen many drugs at once, making the process faster and more efficient. The method is also useful for visualising target engagement in preclinical models, providing a better understanding of how drugs work in complex biological systems.”
Next step
The research team is excited about the possibilities that the CeTEAM method offers. Future steps include understanding why certain protein variants work better for the method, expanding its use to different types of drugs, and exploring drug target selectivity in cells. Nicholas Valerie emphasises, “This method could lead to more efficient discovery of new drugs that benefit patients across various diseases.”
The study was primarily funded by Barncancerfonden, Cancerfonden, Cancer Research KI, Science for Life Laboratory, the Hållsten Foundation, the Novo Nordisk Foundation, and the Marie Skłodowska-Curie Actions (MSCA) Innovative Training Network (ITN) – CANCERPREV, and involved collaborations with other groups at Karolinska Institutet and SciLifeLab, Stockholm University, and the University of Montreal.
Publication
Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM
Nicholas C. K. Valerie, Kumar Sanjiv, Oliver Mortusewicz, Si Min Zhang, Seher Alam, Maria J. Pires, Hannah Stigsdotter, Azita Rasti, Marie-France Langelier, Daniel Rehling, Adam Throup, Oryn Purewal-Sidhu, Matthieu Desroses, Jacob Onireti, Prasad Wakchaure, Ingrid Almlöf, Johan Boström, Luka Bevc, Giorgia Benzi, Pål Stenmark, John M. Pascal, Thomas Helleday, Brent D. G. Page & Mikael Altun
Nature Communications, online 6 december 2024.