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Key Sessions

Janos Kodra

Carbon-Carbon Bond Formation On Peptides

Novo Nordisk A/S, Denmark

08:30 - 09:00 30 mins
09:00 - 09:10 10 mins
Chairperson's Opening Remarks
  • Anish Konkar - Cluster Head, GI Endocrinology & Obesity, Sanofi-Aventis Deutschland GmbH
09:10 - 09:50 40 mins
Phage Selection Of High-Affinity Ligands Based On New Cyclic Peptide Formats
  • Sangram Shivdas Kale - Postdoctoral Researcher, Ecole polytechnique fédérale de Lausanne (EPFL), Switzerland

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.

09:50 - 10:30 40 mins
Genetically- Encoded Peptide Libraries: 48 Hours to Hit Identification
  • Ratmir Derda - Associate Professor, University of Alberta

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.

10:30 - 11:00 30 mins
Morning Coffee Break
11:00 - 11:40 40 mins
Multi-Targeting Peptides For The Treatment Of Obesity And Type 2 Diabetes
  • Anish Konkar - Cluster Head, GI Endocrinology & Obesity, Sanofi-Aventis Deutschland GmbH
11:40 - 12:20 40 mins
Carbon-Carbon Bond Formation On Peptides
  • Janos Kodra - Principal Scientist, Protein & Peptide Chemistry, Novo Nordisk A/S, Denmark

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.

12:20 - 13:00 40 mins
Targeting Protein-Protein Interactions With Peptide-Based Inhibitors
  • Kristian Strømgaard - Professor, Center for Biopharmaceuticals, University of Copenhagen, Denmark

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.

13:00 - 14:00 60 mins
14:00 - 14:40 40 mins
Macrocyclic Peptides – Powerful Therapeutic Modalities for Challenging Targets – From Discovery to Clinics
  • Marc Thommen - Head of Chemistry, Polyphor Ltd, Switzerland

Polyphor’s drug discovery platform will be presented and exemplified with 2 showcases:

  • POL6014 a potent and selective human neutrophil elastase (HNE) inhibitor for chronic treatment in cystic fibrosis and potentially other rare lung diseases. POL6014 is currently in Phase 1b clinical trials and is administered topically (aerosol).
  • POL7080 a pathogen specific (pseudomonas aeruginosa) antimicrobial drug with a novel mode of action. This macrocyclic peptide is about to enter Phase 3 clinical trials in Q1 2018 and is applied systemically (iv). POL7080 has spearheaded our efforts in antimicrobial drug discovery. It prompted a broad spectrum, gram negative OMPTA (Outer Membrane Protein Targeting Antibiotics) program, which has delivered very promising compounds currently in late stage lead optimization.
14:40 - 15:20 40 mins
Engineering Antibody Reactivity for Efficient Derivatization of Tarantula Venom Peptides to Generate NaV1.7 Inhibitory Peptide-Antibody Conjugates
  • Les Miranda - Executive Director Research, Structural Biology, Molecular Modeling, & Hybrid Modality Engineering, Therapeutic Discovery, Amgen Inc.

The voltage-gated sodium channel NaV1.7 is a genetically-validated pain target under investigation for the development of analgesics.  Although there has been considerable effort directed at the identification of a Nav1.7 inhibitory monoclonal antibody, the only reported NaV1.7 targeting monoclonal antibody could not be reproduced1.  As part of efforts to better understand the general potential of utilizing large molecule scaffolds, we pursued an alternate approach to generate a large molecule inhibitor of NaV1.7 function.  In this presentation we describe the engineering of antibodies to facilitate preparation of peptide-antibody conjugates with NaV1.7 inhibitory activity2.

(1) Liu, D. et al. F1000Research 5, 2764.

(2)  Biswas, K. et al. (2017) ACS Chem. Biol., Just Accepted Manuscript.  DOI: 10.1021/acschembio.7b00542

15:20 - 15:50 30 mins
Afternoon Coffee
15:50 - 16:30 40 mins
Tailor-Made Proteins for Biotechnology and Medicine Generated by Semisynthesis
  • Christian Becker - Head of the Institute of Biological Chemistry, University of Vienna

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.

16:30 - 16:35 5 mins
End of Conference Day 1