Today’s drug discovery efforts focus mainly on two major drug classes with clearly distinct properties and applicability: small molecules and biopharmaceuticals. In collaboration with Prof. J. A. Robinson at the University of Zurich, Polyphor has developed a new, proprietary technology, known as Protein Epitope Mimetics (PEM) with the potential to address difficult drug targets by combining the advantages of small molecules and biopharmaceuticals.
PEM are medium sized (0.7-2 kDa), fully synthetic cyclic peptide-like molecules that mimic the two most relevant secondary structure motifs of proteins involved in Protein-Protein Interactions (PPIs): The ?-hairpin and the ?-helix. Hence, PEM molecules can be viewed as functional minimizations of proteins. The PEM are among the most potent and selective molecules known to modulate PPIs, GPCRs (define at first use) with large ligand-binding domains and enzymes. PEM Technology is, therefore, well suited to discover and optimize drug candidates that interfere with targets difficult to modulate with classical small molecule approaches (for a review see: J. A. Robinson et al Drug Discov. Today 2008, 13, 944-951; D. Obrecht et al. Curr. Med. Chem. 2009, 16, 42-65).
PEM molecules are readily accessible by Polyphor’s multi-parallel synthesis technology for the production of focused PEM libraries. Several elements of the molecule can be varied in the library design in order to optimize potency, selectivity, and ADMET properties.
Polyphor and Prof. J. A. Robinson jointly developed a number of proprietary templates for the induction and stabilization of the ?-hairpin conformation of peptide backbones comprising up to 20 amino acid residues. The ?-hairpin conformation is important for a potent and selective inhibition of PPIs, GPCRs, ion channels and enzymes. Polyphor routinely uses high-field NMR to elucidate the conformation of PEM molecules in order to establish a 3D-SAR (define). The following target/ligand-based design inputs were successfully used as starting points for PEM design:
- Natural peptide sequences
- Phage peptides
- Key peptide motifs (RGD; WKY, etc.)
- Key pharmacophores (turn-like; helical)
- Site-directed mutagenesis data (epitope mapping)
- X-ray/NMR structural analysis of ligands and target molecules
An interesting application of an extensive pharmacophore analysis using PEM Technology has been published (J. A. Robinson et al., Angew. Chem. 2004, 116, 2161-2164; R. Fasan et al., ChemBioChem 2006, 7, 515-26.). A PEM inhibitor of the p53/ HDM2 interaction was derived from the native functional epitope of the tumor suppressor p53. Co-crystallization and X-ray analysis of HDM2 and the PEM inhibitor revealed not only detailed structural information on the binding interface, but also that the PEM ligand explores a new pharmacophore not used by the natural helical ligand.
The proprietary PEM Technology has allowed Polyphor to build a broad clinical candidate pipeline. Encouraging results have been obtained in our proof-of-concept studies and in-house drug discovery programs. Polyphor is interested in partnering these innovative programs.
Polyphor has also developed PEMfinder®, a proprietary, diverse library composed of >30’000 PEM molecules targeting GPCRs, ion channels, enzymes and other difficult targets. This drug discovery tool has been successfully used by Polyphor in internal programs and collaborations with Pharma companies for hit identification on targets where previous small molecule drug discovery approaches had failed.