Looking for drugs amongst exotic peptides

In the realm of the proteome, it’s shape rather than size that matters. Perth-based drug-discovery biotech Phylogica believes it has just about every possible molecular contingency covered.

Phylogica was founded in 2001 to commercialise proprietary functional proteomic drug-discovery technologies developed by Perth’s Telethon Institute for Child Health Research, and the Fox Chase Cancer Centre in Philadelphia, Pennsylvania.

The company recently appointed Dr Stewart Washer as its new CEO. Back from a trans-Tasman tour of duty at the helm of New Zealand biotech flagship Celentis, Washer is preparing the company for an IPO in November.

‘Phylogica’ derives from taxonomy’s term ‘phylum’. The Phylomer library exploits the proteomic diversity of the two most ancient branches of the tree of life, the phyla Eubacteria and Archaea.

The phylum Archea includes some of the world’s hardiest single-celled life forms – the “extremophiles” that inhabit the boiling waters of thermal springs and oceanic rift vents, hypersaline lakes, acidic mine-tailings dumps and other hostile environments.

“We selected the extreme branches of the phylogenetic tree and went out and got these weird bugs with very diverse genomes,” Washer said.

Phylogica researchers made three different digests of the composite “mega-genome” of these microbes, to generate its library of 60 million peptides in the 20 to 30 amino-acid size range.

Washer said the library represents most, if not all, the possible peptide shapes that exist in nature, so for any chosen target there are likely to be multiple matches.

The Phylomer library was the source of all three of the company’s lead compounds, for asthma, stroke and breast cancer. In addition to its own drug-discovery program, Phylogica offers a service to clients looking for ligands for promising drug targets.

Phylogica’s Discriminator Blocker Trap, a modified reverse yeast-hybrid system, provides the means to screen the vast Phylomer peptide library for molecular mates for target molecules. Washer says the technology can be used to discover high-specificity peptide mimetics that will either activate or silence drug targets such as receptors.

The Discriminator Blocker Trap allows huge numbers of Phylomer peptides to be screened rapidly for promising activity against therapeutic targets.

It involves mating a transgenic yeast strain expressing the target molecule to a multiplicity of yeast strains expressing Phylomer peptides.

Random matings bring each Phylomer peptide together with the target.

Promising therapeutic peptides are identified when a ‘match’ activates a survival pathway that spares the yeast cell, while all unsuccessful hybrids die off.

“The exciting thing is that there are so many proteomics companies around now, and they’re our commercial fuel,” Washer said. “We can take their targets, thrown them into our discriminator blocker trap, and find peptide drug candidates.”

Washer said the ‘alien’ peptides derived from extremophile proteins are much more likely to yield new drug candidates than peptides derived from human proteins, because human proteins have been selected through evolution for very specific tasks.

“So in order to find a peptide to block a protein disease interaction in humans, you need to go to the ends of the evolutionary tree,” he said.

Washer said that the market was “probably sick of platform technologies”, but in Phylogica’s case, the platform technology was highly product-focused.

“We’re not trying to hawk our technology, or sub-license it. We’re looking for specific co-development opportunities.”

Washer said Phylogica’s stroke-protection candidate peptide inhibits one of the cell-signalling kinases involved in the cascade of events that triggers the death of healthy neurons after stroke. The ‘penumbra effect’, the mass-death of healthy neurons around the site of the primary injury, can have devastating neurological consequences.

The company has also identified several promising peptide mimetics to the antigens, DerP1 and DerP2, for a vaccine to protect asthma patients with an allergy to dust-mite excreta, the most common trigger for asthma attacks.

Phylogica has also identified two peptides with potential activity against breast cancer – they target the telomerase pathway, forcing cancerous cells shut down and die.

The company has 10 researchers, all fully funded by international grants including one the National Institute of Health in the US (NIH).