The research team is harnessing the power of ribosomes to develop chemical libraries

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graphic abstract. credit: ACS Science Central (2023). DOI: 10.1021/acscentsci.3c00316

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graphic abstract. credit: ACS Science Central (2023). DOI: 10.1021/acscentsci.3c00316

A research team led by UC Irvine scientists has developed an innovative method to quickly and efficiently create broad groups of chemical compounds used in drug discovery by harnessing the power of ribosomes, the molecules in all cells that make proteins and peptides.

Results recently published in ACS Science Central describe this transformative technology, which can replace the current intensive manual process, accelerating the discovery of new drugs that can impact the treatment of a wide range of diseases and conditions.

Chemical libraries are collections of molecules that are screened to identify those with promising activity or therapeutic potential. Screening involves asking the same biological question for every chemical in the library in the form of a quick experiment or quiz.

“Synthesis and screening of the library are the first steps in discovering new drugs,” said Brian M. Pagel, professor of pharmaceutical sciences at UCLA and co-author of the study. “This new technology allows us to assemble libraries of extremely miniaturized gel beads that each contain hundreds of thousands of copies of a single compound from the library. Arranging many copies of the molecules on the beads allows scientists to directly assess the biological activity of each member of the library, an invaluable ability.” invaluable in the search for new drugs.”

The team devised a new method for generating gel beads roughly the size of a human cell, each containing massive amounts of ribosomes, an enzyme called RNA polymerase and a magnetic core decorated with DNA, not unlike the nucleus of a human cell. DNA cores encode or provide assembly instructions for specific peptide molecules. Insulin is an example of a naturally occurring peptide that has become a drug.

By simulating the flow of a cell’s genetic information from DNA to RNA to peptide synthesis, the researchers succeeded in pinpointing the location of genetically encoded peptide synthesis within each individual bead. Importantly, this technique can be performed in parallel on millions of beads, each bearing a unique DNA tag, forming an expansive library.

“The beads themselves are also an important achievement. The ribosome facilitates a chemical manufacturing process that currently relies on manual, labor-intensive procedures, allowing us to prepare very large libraries using nature as our inspiration. Scientists can now explore a large number of molecules,” said Paigel, who has Also appointments in chemistry and biomedical engineering: “At the same time, this advances pharmaceutical discoveries, while DNA-encoded magnetic cores enable efficient tracking and analysis of individual compounds.”

The method also has applications in other fields, such as engineering enzymes, developing environmentally friendly pesticides, or creating materials with specific physical properties.

Other team members included co-authors Christian Cunningham and Alex Chan, both scientists at Genentech in South San Francisco, and Valerie Cavett, UCI’s project specialist in pharmaceutical sciences.

more information:
Valerie Cavite et al., Hydrogel-coated beads enable proximity-dependent synthesis and screening of the encoded library, ACS Science Central (2023). DOI: 10.1021/acscentsci.3c00316

Journal information:
ACS Science Central

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