In many ways, a scientist’s search for the right compound to target the right cells in the body is a game of numbers – the more likely candidates that can be identified the better the chances that the right compound with the most potential to inhibit or otherwise impact the target will be found.
“It’s not unlike the Lotto – the more tickets you buy, the more likely you’ll have a winner,” says Julio Camarero, lead author of a new study published in Angewandte Chemie, the world’s highest impact chemistry-specific journal published by Wiley for the German Chemical Society. The journal report features groundbreaking work by Camarero and colleagues on a novel process that allows in-cell molecular evolution strategies that are able to screen huge libraries of molecules.
In-cell molecular evolution provides the opportunity to evaluate millions of compounds and to identify those with the best potential to bind and inhibit targets. Genetically encoded libraries of cells provide optimal opportunities to create and screen very large combinations of molecules.
“To our knowledge, this is the first time a natural cyclotide containing unnatural amino acids has been produced inside a living cell,” says Camarero. “This allows for development of new biological functions, such as using fluorescent probes for in-cell production of fluorescently-labeled cyclotides for screening or probing molecular interactions using optical approaches.”
Camarero’s work holds promise for drug and diagnostic tool design since it leads to the potential for in vitro as well as in vivo screening of millions, even billions, of compounds and the rapid identification of novel sequences that are able to bind to specific targets. The process has many applications since it allows for broad-range screening and for potential altering of their structures to generate novel binding activities to better target proteins.
“This provides a fast way to interrogate huge numbers of cells and to ascertain which ones are talking to our target,” says Camarero whose work is supported by the National Institutes of Health, Department of Defense and Bristol-Myers Squibb.
Cyclotides are natural plant proteins that are small, easy-to-make molecules with a potential to be used as a substitute for antibodies which are unstable and difficult to make. Camarero’s process for making them in the cell presents an enormous boon to accelerating the identification of the right compound for a specific target.
Ultimately, this work has implications for development of therapeutics and diagnostics tools for better treatment and early detection of human diseases. The process is unique and can be used for multiple applications to expedite bench research to patient care.
“The development of this new biochemical technology for the production of fluorescent-labeled cyclic peptides in biological systems is opening new and exciting opportunities that before were restricted only to synthetic chemists,” said Camarero.
This technology allows for the creation of genetically encoded libraries, opening the door for not only chemists but also for biologists and other scientists to pursue research that will potentially decode complex biochemical pathways and protein interactions in living cells.
Along with lead author Julio Camarero, the study authors include colleagues in his lab, the USC Department of Chemistry, the Salk Institute of Biological Studies, Department of Chemistry at the State University of New York-Albany.
To read the journal report, go to http://dx.doi.org/10.1002/anie.201209219.