We will test the hypothesis that we can rapidly develop oligomeric ligands with low conformational entropy that bind shallow crevices and grooves on protein surfaces with high affinity (Kd <10 nM) by sequentially expanding a pharmacophore on the oligomer. We will start with a peptide with a known bound structure and transfer the key side-chains of the peptide pharmacophore onto an oligomeric bis-peptide scaffold to create molecules with moderate or good affinity for the target protein. We will then extend the bis-peptide one monomer at a time and screen a small number of monomer stereoisomers and side-chains to identify ligands with better affinity for the receptor. By repeating this process two or three times we will identify bis-peptide based ligands with low nanomolar or subnanomolar dissociation constants for the target receptor. We will test the hypothesis on three target proteins: hDMX, HIV gp41 and the seven-transmembrane bound G-protein coupled receptor GLP-1R. We will then collaborate with others to evaluate the in vivo activity of these compounds.
The protein binding bis-peptide ligands that we develop will modulate the functions of the proteins they bind by disrupting protein-protein interactions. They will be useful tools for biologists to study the roles of the target proteins in cells. They may also be developed as new therapeutics for diseases that involve the target proteins. We will develop bis-peptides that target three proteins. The first target is hDMX a protein involved in cancer. The second target is HIV gp41, we will develop bis-peptides that prevent fusion of HIV with human cells and could be used to treat HIV. The third target is the seven-transmembrane G-protein coupled receptor GLP-1R: we will develop bis-peptides that act as agonists and antagonists of GLP-1R which could be used to treat type 2 diabetes.