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Phylomers: A Powerful Toolbox for Discovery of Therapeutic Peptides

Phylomers are a new class of peptide derived from genomes of biodiverse archael and bacterial species, which are highly enriched for structural motifs, including those found in thermostable proteins. This approach exploits the structural information found in abundance within natural proteins, which have evolved for high affinity and specific interaction with protein interfaces and also biological activity. By integrating these libraries with various high throughput screening platforms, such as yeast two hybrid, phage display and phenotypic screening formats, we can rapidly interrogate the vast majority of subdomain structures found in nature. Moreover, as phylomer libraries are constructed using fully-sequenced genomes, we can use bioinformatic approaches to model structure-activity relationships and fast-track lead optimization strategies.

We?ve shown that phylomer libraries can provide a rich source of binders against a broad range of target classes, presumably through containing more privileged structures. These include binders to extracellular protein domains such as the CD40L receptor, where we have identified several hits with picomolar binding affinities, as well a panel of primary hits that show potent biological activity against various intracellular targets prior to affinity maturation. Using the classical TAT CPP for intracellular delivery of cargoes, we have validated the efficacy of therapeutic phylomers against intracellular targets in animal models of stroke, traumatic brain injury, acute respiratory distress syndrome and acute burns.
In collaboration with Roche, Phylogica has also screened its phylomer libraries to discover novel classes of cell penetrating peptides (CPPs). This research has yielded a number of distinct structural families of CPPs, which appear to use a range of different cell uptake mechanisms. Several cell-selective CPPs were also identified, highlighting the potential for this approach to deliver therapeutic payloads to specific cell types. Visit the Phylogica Website ?