Scientists at Scripps Research have developed a new approach for discovering targeted drugs that can change the function of proteins. Their research, published in Molecular Cell, demonstrates an improvement over previous methods for identifying small molecules that selectively attach to proteins, but not whether they affect the proteins' biological activities.
The new method involves using two mirror-image versions of a small molecule and comparing how they change the size of protein complexes in cells. This approach expands the ability to discover small molecules that not only bind proteins but also have functional impacts.
The team used the conglomeration of proteins into complexes as a proxy for their function. By designing pairs of stereoisomers, the scientists could each bind irreversibly to proteins and be sure that the impact of each small molecule was due to its unique structure.
The researchers tested whether a protein-of-interest was in a different size complex by exposing cells to the pairs of stereoisomers and using size exclusion chromatography in which proteins are sifted through beads with different sized pores.
The team screened a set of small molecules for their ability to change the sizes of protein complexes in prostate cancer cells. They pinpointed a molecule, MY-1B, which selectively disrupted a complex of proteins known as PA28, previously found to play a role in degrading proteins in cancer. They also discovered that a different chemical, EV-96, changed the size of a protein complex involved in splicing strands of RNA inside cells, slowing the growth of cancer cells, and pinpointed SF3B1 as the protein the chemical was binding to.
According to the research team, the new chemicals represent the first time scientists have been able to target the protein complexes with small, simple synthetic chemicals. This approach provides researchers with new chemical tools in their arsenal, offering new ways to better understand these proteins and investigate potential therapeutic opportunities.