October 22, 2021 -- A "three-headed hydra" significantly improves efficacy in targeted protein degradation, according to research published October 21 in Nature Chemical Biology.
Researchers from the University of Dundee in Scotland and Promega developed the trivalent proteolysis-targeting chimeras (PROTACs), which they say opens new possibilities for drug discovery for cancer and other targets.
PROTACs are usually designed with two heads. They are being trialed as candidate medicines against various cancers and are progressing through clinical trials.
The Dundee/Promega team, however, adopted a three-headed approach, which shows stronger anti-cancer activity in cellular studies at a lower dose and improved pharmacological responses over a wider dose range, according to the study. Researchers designed the trivalent PROTACs by adding an additional protein-binding ligand.
The Dundee/Promega team demonstrated that the new PROTAC works due to the combined effect of avidity (the cumulative strength of multiple interactions between two molecules) and cooperativity (a phenomenon exhibited by molecules with multiple binding sites in which the affinity of the remaining bindings sites is increased after a ligand binds to one of the sites). Avidity and cooperativity, the researchers said, are two important features of protein and small molecule molecular recognition.