A team led by researchers at the University of Toronto has created a platform, called SIMPL2, that revolutionizes the study of protein-protein interactions by simplifying detection and improving measurement accuracy.
Protein interactions play an important role in biological processes, including those involved in diseases. The team behind the SIMPL2 platform designed it to optimize researchers’ ability to measure protein-protein interactions for targeted drug therapies. While protein-protein interactions were previously considered “non-drug” using small molecules, the platform addresses this challenge by making it easier to measure these interactions, improving our understanding of the types of molecules needed to control them.
“Many methods have been developed to measure protein interactions, especially more recently as the importance of protein interactions in diseases has become more evident,” he said. Zhongyaofirst author of the study and senior research associate at U of T’s Donnelly Center for Cellular and Biomolecular Research. “However, all of these methods have disadvantages, including high costs and complicated procedures that delay results. The biggest advantages of our SIMPL2 platform are that it produces more reliable measurements and is comparatively cheaper to use.
The study was recently published in the journal Molecular systems biology.
Yao began working on the protein interaction measurement problem while developing the original SIMPL (split-intein medicinal protein ligation) system. SIMPL2 is an update of SIMPL involving the use of the split luciferase enzyme for detection of protein interactions by luminescence. In addition to improving the identification of interactions, the entire measurement process occurs through a medium: the liquid. This greatly simplifies the process by reducing the number of steps required to perform measurements.
“One of the problems with SIMPL was that we had to use an additional process, called ELISA, to identify proteins spliced by the SIMPL platform,” Yao said. “It was a painful process that made an otherwise effective technology more complicated and expensive to use than necessary. SIMPL2 only requires one step, which can be performed manually, or can be automated for even greater efficiency in high-performance studies.”
To test the sensitivity and applicability of the new platform, the research team used it to measure interactions between proteins affected by modulators. Protein modulators include molecules that inhibit protein interactions, those that facilitate protein interactions, and those that facilitate the degradation of target proteins. SIMPL2 was found to perform well in identifying these interactions, even in cases where the interactions were weak.
While quantum computers and artificial intelligence have made it easier to design small molecules for drug therapies, this has led to the need to develop much faster methods to validate the efficacy of new drugs. SIMPL2 may fill that need, as it can be used to test interactions between new molecules and their target proteins in cultured human cells. It is also capable of following the pace at which new molecules are designed.
“We designed SIMPL2 to be a universal method for studying protein interactions that is rapid and inexpensive, as well as highly sensitive,” he said. Igor Stagljarprincipal investigator of the study and professor of biochemistry at U of T’s Temerty School of Medicine. “Now that we have optimized the platform, our next step is to use it to study interactions that play key roles in diseases, such as cancer, to learn how develop drug therapies. This work will involve the use of quantum computers and artificial intelligence in collaboration with Alán Aspuru-Guzik’s laboratory at U of T and Insilico Medicine, a world leader in generative AI drug discovery.
This research was supported by FACIT and Ontario Genomics.