'Pseudo-cyclic Phylomer libraries through loop engineering of a display scaffold'
Shane Stone* 1, 2 , Tatjana Heinrich 1, 2 , Paula Cunningham 1, 2 , Paul Watt 2, Katrin Hoffmann 2 , Richard Hopkins 2 1 Telethon Kids Institute, Australia; 2 Phylogica, Australia
We are developing a novel way to generate genetically encoded cyclic Phylomer libraries through the loop engineering of a display scaffold. Phylomer libraries are collections of peptides that are derived from fragments of biodiverse microbial genomes and cover vast structural and sequence space. Given their genomic source, Phylomers are enriched for structure and have evolved for protein-protein interactions, making them an ideal screening resource against protein targets. Cyclisation of peptides confers appealing drug-like properties such as increased structural stability, protease resistance, increased serum stability and half-life, and extending to improved target affinities. In essence, cyclisation improves the druggability potential of a peptide and incorporating this into a screening platform could vastly improve the quality of hits. Classic peptide cyclisation requires covalent linkage between the termini or side chains of a peptide sequence, which is difficult to achieve in a genetically encoded environment. Instead we have engineered a loop of a stable scaffold to display Phylomer peptides, where the intrinsic structural stability of the scaffold constrains the termini of the Phylomer sequence in close proximity, consequently conferring pseudo-cyclic characteristics to the display loop. We have undertaken a range of proof-of-concept studies of our cyclic Phylomer display platform and present evidence validating the concept along with several potential applications.
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