Peptides are a unique group of molecules. The 20 natural amino acids, along with many more non-natural amino acids and a series of post-translational modifications such as sugar and lipid incorporation enable us to generate incredibly diverse molecules which the body sees as natural. This means that our immune system is generally tolerant of them and they can pass safely through the body without accumulation.
Peptides have the exquisite selectivity of other biologics such as antibodies but are much smaller – making them both easier to manufacture and able to reach places that antibodies can’t. In addition, they break down to amino acids which are easily eliminated.
Peptides are highly active biological molecules that offer great potential as drugs due to their high specificity, low toxicity and low manufacturing costs that confers upon them the advantages of both small molecule and large biological based therapeutics.
Peptide Therapeutics has been greatly enhanced by the evolution of display technologies. These technologies enable the move from peptide discovery which uses endogenous peptides as a starting point to discovery which uses large, random libraries to identify novel structures. This means we can address targets for which there is no known peptide binder.
Phage and yeast display technologies are dependent upon a biological host and while sensitive this dependency can lead to replication bias and interference from native host proteins and are limited to the incorporation on only natural amino acids. Improved in vitro methods based on ribosomal and mRNA display have overcome some of the shortcomings of phage and yeast display and have introduced the ability to incorporate some non-natural amino acids into peptides. These technologies can be limited by the number of peptide copies that are displayed (phage 5, mRNA 1) meaning that they suffer in terms of the detection of low affinity binders.
Orbit Peptide Display makes the next step in this evolution – it presents natural, non-natural, constrained and modified peptides to both purified and cell-surface targets and so is the technology able to address the broadest range of potential drug targets.
Orbit’s Peptide Display was conceived at the Weatherall Institute of Molecular Medicine in Oxford by Professors Ogg and Rabbitts. At that time (2014) there was a lack of technology to support the growing need to present and screen peptide libraries against live cells.
This new technology had all the positive attributes of phage display and in-vitro display methods whilst maintaining low background binding and excellent display density. In 2015, Orbit Discovery kicked off as a spin-out from Oxford University.
Our in vitro display technology uses small beads to link randomised peptide sequences to the DNA which encodes them. A DNA library is constructed which codes for a scaffold and the random or semi-randomised peptide sequence. Each piece of DNA in the library is attached to a bead so that each bead holds just one sequence.
In vitro transcription/translation results in a library of beads, each of which displays several thousand copies of its specific peptide.
The Orbit Peptide Display technology has the positive attributes of in vitro display, such as a cell-free environment and highly diverse libraries, combined with the sensitivity of in vivo methods.
Our technology allows for the introduction of non-natural amino acids into peptides and also the generation of cyclic, bicyclic and tricyclic peptides and the introduction of other constraints. Cyclic peptides are more stable and have potentially higher affinity and specificity compared to their linear counterparts. Further increases in stability and chemical diversity can be achieved by incorporation of methylated amino acids, D-amino acids and click chemistries that allow for post translational modifications.
Additionally, the Orbit technology is amenable to cell surface screening, enabling direct screening of cell surface target binding and subsequent functional cellular responses.