Medicines that travel directly to a tumor or other target in the body hold great promise for the treatment of cancer and other diseases. Targeted medications have the potential to be highly effective at reduced doses, dramatically reducing side effects for the patient and improving quality of life. But attaching these “molecular address labels” to drug molecules has proved difficult. Tom Muir, Princeton’s Van Zandt Williams Jr. Class of 1965 Professor of Chemistry, and his collaborators Associate Research Scholar Miquel Vila-Perello, Postdoctoral Research Associate Zhihua Liu and graduate student Neel Shah have developed a new technique for fastening these targeting molecules to drugs and building these so-called drug-antibody conjugates.
The method relies on naturally occurring proteins, called “split inteins,” found in a certain type of blue-green algae. Split inteins come in pairs that can bind each other tightly like opposing strips of Velcro. Muir’s team found an efficient way to attach one intein to the targeting molecule, which is an antibody that selectively binds to the desired cells, while using the matching intein to attach the drug molecule to it. Mixing the antibodyintein with its complementary intein, in the presence of the drug, allows the matching inteins to come together and facilitates the tight attachment of the drug to the antibody.
“With this new split intein-based method, we have an exciting and important way to generate targeted drugs,” said Muir. The research was supported by grants from the National Institutes of Health.