There is increasing interest in the development of covalent ligands of proteins, which have many advantages over non-covalent ligands. The goal of this proposal is to develop large libraries of DNA-encoded libraries of potential covalent ligands and to optimize methods to screen them. This would represent a major advance over current technology to identify covalent ligands, which almost always relies on structure-aided grafting of an electrophile onto an existing reversible ligand. The successful completion of this Phase I effort would establish a platform that Deluge could offer customers in the form of a custom screening service for the identification of potent and selective covalent ligands for any protein of interest to the customer that has surface-accessible cysteines.
There is increasing intense interest in the discovery of drug leads that engage protein targets covalently, since they generally display higher potency and longer residence times than non-covalent ligands. We will optimize protocols to create and screen a DNA-encoded library of about three million novel compounds, all containing an ?-cyanoacrylamide warhead that reacts covalently, but reversibly, with cysteine thiols. The goal at the conclusion of this Phase I effort will be to establish a streamlined operation that can be offered to customers as a custom screening service.
