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A Strategy for Synthesizing Potential New Drugs and Research Tools Yields Insights into Fat Cell Development

With a creative strategy for generating new knowledge that may lead to future drug development, researchers developed a set of small chemicals that bind many different proteins in cells and can be used to learn the proteins’ functions. Using this approach, they discovered a protein important in fat cell development.

Different types of proteins perform key tasks throughout the body, and many drugs are chemicals that target specific proteins, either blocking or increasing their functions for therapeutic effects. Chemicals that bind to proteins can also be used to gain new understanding of what the respective proteins do. However, only a fraction of human proteins are targets of current drugs. Thus, scientists devised a way to target many previously untargeted proteins with small chemicals. To get a sense of how many proteins could be targeted this way, they developed a collection of small chemicals of varying structure (which they also called “fragments”), each with a special tag, and mixed these with human cells grown in the lab. Using the tags, they retrieved the chemical-protein pairs that formed in the cells. In their initial screen, they identified thousands of interactions between the chemicals and different types of proteins; each chemical could bind multiple proteins. A search of a large database revealed that most of these proteins were not targets of existing drugs. These results showed that a large variety of proteins—more than previously thought possible—could be bound by small chemicals. Further experiments with a few of the chemicals showed that these inhibited the functions of the bound proteins. The researchers also found that, by modifying a chemical’s structure, they could strengthen its interaction with a particular protein of interest, an approach similar to the methods scientists use to fine-tune the structure of a potential new drug.

The researchers then explored whether their small, tagged chemicals could be used to discover proteins important for biological processes. As a test case, they chose the process of fat cell development. They screened for chemicals that could prompt precursor (immature) cells from mice to develop into fully mature fat cells. They found one chemical that could do this; identified the protein it bound, PGRMC2; and showed that the chemical stimulated the protein’s activity. Through these and additional experiments, they discovered that PGRMC2 plays a role in fat cell development.

This research demonstrates that small, tagged chemicals can be used to target a wide variety of proteins in human cells. Future studies may advance understanding of the proteins they bind, and these chemicals could potentially serve as starting points for new drug development.