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Carbon-Carbon Bond Formation On Peptides
Novo Nordisk A/S, Denmark
Bicyclic peptides offer an attractive modality for the development of therapeutics. They can be developed by a procedure based on phage display in which linear peptides on the tip of phage are chemically cyclized prior to affinity selection. In my talk, I will present new chemical peptide cyclization strategies that we had developed recently and their application for the phage selection of high-affinity ligands.
Our group uses genetically-encoded (GE) libraries of peptides as a starting material for organic synthesis to produce libraries of peptide derivatives.1,2 These chemical modifications allowed us to develop Genetically-Encoded Fragment-Based Discovery (GE-FBD) platform,3 which combines >108 peptide fragments with silently-encoded modifications.4 I will share our vision and technologies we develop to maximize the reproducibility of discovery within genetically-encoded library framework.
Carbon-carbon bond construction is the basis for all of organic chemistry, given the multifunctional nature of peptides and the limited solubility of peptides in typical organic solvents, has limited the amount of carbon-carbon bound forming reactions that currently are being used routinely in combination with peptide chemistry and only a few examples exist on ligating peptide fragments based on Carbon-Carbon bond formation. The talk will focus on our work using organic catalysis to form Carbon-Carbon bonds on bioactive peptides.
Protein-protein interactions (PPIs) are essential to vital cellular processes, and serve as potential targets for therapeutic intervention. We are particularly interested in the PPIs between integral membrane proteins and their intracellular protein partners. We have developed peptide-based inhibitors of the PSD-95/glutamate receptor interaction, by exploiting that PSD-95 contains a tandem PDZ1-2 domain. So we designed and synthesized dimeric peptides with low nanomolar affinities, and have demonstrated that these ligands are potential treatment for ischemic stroke. For the same PPI, we examined the importance of backbone hydrogen bond by employing amide-to-ester mutations in peptide ligands and proteins. Finally, we have exploited the principle of dimeric peptide-based ligands to perturb the PPI between the scaffolding protein gephyrin and glycine/GABAA receptors. Most recently we have developed high affinity, cell-permeable peptides and demonstrated how these can modulate receptors and used to label synapses.
Polyphor’s drug discovery platform will be presented and exemplified with 2 showcases:
The ability to produce proteins in the laboratory and to change their structures and therefore their properties in a controlled fashion is of crucial importance in basic biological research, in biotechnology and increasingly in medical applications. I will discuss our efforts to use chemoselective ligation methods to assemble posttranslationally modified proteins from a combination of synthetic peptides and protein segments produced by expression (protein semisynthesis). Examples will include the semisynthesis of lipid-modified, membrane-attached proteins, of glycosylated peptides and proteins as well as proteins with non-enzymatic modifications.