DNA-decoded Libraries of Reversible, Covalent Protein Ligands

Project Summary There is increasing interest in the development of covalent ligands of proteinswhich have many advantages over non covalent ligandsThe goal of this proposal is to develop large libraries of DNA encoded libraries of potential covalent ligands and to optimize methods to screen themThis would represent a major advance over current technology to identify covalent ligandswhich almost always relies on structure aided grafting of an electrophile onto an existing reversible ligandThe 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 Project Narrative There is increasing intense interest in the discovery of drug leads that engage protein targets covalentlysince they generally display higher potency and longer residence times than non covalent ligandsWe will optimize protocols to create and screen a DNA encoded library of about three million novel compoundsall containing ancyanoacrylamide warhead that reacts covalentlybut reversiblywith cysteine thiolsThe 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