Discovery Lead, Orbit Discovery
High Throughput Selection of Peptides with Biological Function
Peptides are highly active biological molecules that, with advances in stability and delivery, present huge potential as drug candidates. They possess the advantages of biological and small molecule drugs due to their high specificity, low toxicity and low manufacturing costs. Currently, peptide therapeutics comprise just 5% of the pharmaceutical market and 1% of prescribed drugs. With an increased interest in the use of peptides as therapeutics comes the need for strategies to allow for the discovery of novel hit candidates, in a high throughput manner, from highly complex peptide libraries.
Current technologies for the discovery of novel peptide therapeutics include phage, yeast, ribosomal and mRNA display but these all hold their own limitations. Phage and yeast display are sensitive but a reliance upon a biological host can result in replication bias and interference from native host proteins. These systems are also restricted to the use of natural amino acids. In vitro technologies based on mRNA and ribosomal display have the ability to incorporate unnatural amino acids but are limited by small peptide copy number leading to a reduced detection of low affinity binders. Moreover, none of the current peptide display technologies can effectively address cell surface targets for the discovery of functional peptides.
The ORBIT in vitro display technology uses beads to present randomised peptide sequences and the DNA which encodes them, thereby linking genotype to phenotype, and combines the advantages of in vitro display, such as highly diverse libraries and a cell-free environment, with the high sensitivity of in vivo technologies. The ORBIT display platform presents thousands of identical peptide copies per bead allowing for the discovery of low affinity binders and allows for the incorporation of unnatural amino acids and the generation of cyclic peptides which can increase chemical diversity and improve stability, specificity and affinity. In addition to screening for binding peptides, the ORBIT platform can be adapted to screen whole cell surfaces for peptides which elicit functional cellular responses.
In summary, the ORBIT peptide display platform offers peptide drug screening with high diversity, sensitivity and plasticity, and has the potential to discover novel, selective and functional peptide therapeutic leads with a broad target coverage, including cell surface targets, for a wide range of diseases.
Zeke Nims obtained his Ph.D. from UMass Amherst, focused on plant natural product biosynthesis, followed by a postdoc at MIT investigating alkaloid pathway regulation to incorporate non-natural precursors to produce analogs. Zeke joined RaPharma in 2011, focused on interpretation of mRNA display selections using illumina sequencing, and then moved to IPSEN to set up a phage display laboratory. Zeke has been at ORBIT for 2 years, focused on optimizing and industrializing the ORBIT discovery platform.