To improve the potency of CHA-061, the prototype peptide inhibitor of CDA1

This project seeks to further improve the behavior of our prototype peptide inhibitor CHA-061 against the profibrotic effect of CDA1. CHA-061 is a Retro Inverso D amino acid peptide containing a short sequence of a newly identified CDA1 binding protein and a previously described “Cell Penetrating Peptide” (CPP). The CDA1 binding protein part of the CHA-061 inhibitor competitively binds to CDA1 leading to inhibition of formation of the CDA1 complex with its key binding partner protein in the cells. The CPP part of CHA-061 assists with cellular entry of the inhibitor. The theme of this project is to modify this prototype peptide inhibitor and/or to convert it, based on the structure of the CDA1/CHA-061 binding interface, to a new orally bioavailable small molecule inhibitor. The approaches include screening residue substitution derivative peptides using relevant assays (both cell-free and cell based assays), solving CDA1/CHA-061 binding structures by crystallography, medicinal chemistry modification and screening for low molecular weight chemical fragments which bind to CDA1 (Fragment-based Lead Discovery, or FBLD). This is an ideal project for a researcher interested in pharmacology, structural biology and drug discovery. Top-up scholarship is available from the department on a competitive basis.