'PROTEIN-i' LIBRARY

 

Comprised of highly diverse (109) 3D protein-folds. Each ‘shape’ is delivered into an individual livecell (DNA-encoded), which then docks to a complementary 3D-site within a host-cell protein

SITE SEEKER

Phenotypic mining 

Any 3D-folds that dock with a host cell protein and elicit a desired ‘phenotype’ are collected and identified by high throughput DNA sequencing

SITE SECURE

Target capture 

Active protein-folds also have sufficient affinity to then isolate the target protein(s) from inside a cell, which can then be identified using mass spectrometry

SITE BLOCK

SBDD/Competition assay 

 The newly isolated target & 3D protein-fold then informs the rational design or screening of drugs that will recapitulate the desired phenotype in a therapeutically relevant way

OUR RESEARCH

Advances in genomics and basic research are providing a long list of clear causes that lie at the heart of a range of debilitating diseases. This has the potential to open the door to many new and improved targeted therapies. However, many of these newly characterized disease targets are intractable to current drug discovery technologies.  PhoreMost is aiming to remove these barriers to new drug development with its novel SITESEEKER technology, a live-cell phenotypic assay system that can rapidly identify unexpected, or “cryptic” druggable sites in specific disease driving targets and pathways that can’t be readily seen using conventional non-cell based analytical methods.
 

GENOME EDITING

 

GE Libraries e.g., CRISPR:
  • High Target Specificity
  • Only ~25,000 genes
  • Therefore simple assay formats
  • New drug sites not identified

RNAi

 

RNA-i Libraries
  • Low Target Specificity
  • Only ~25,000 genes
  • Therefore simple assay formats
  • New drug sites not identified

PROTEIN-i

 

PROTEIN-i Libraries (USP #1)
  • High Target Specificity
  • Billions of different protein conformations
  • High-level phenotypic assay formats (USP #2)
  • New drug sites identified

 

OUR TECHNOLOGY

Drug targets are like cliff faces; chemists need to find key hand and foot holds on a protein’s surface in order to design small molecule drugs that modulate their function, and thus impact the biological pathways associated with a disease.  At first glance, however, most disease targets appear as sheer glass surfaces, with no obvious routes to attack them. 

This is the picture that researchers all too often see when targets are viewed in isolation outside of a cell, especially in static crystal structures that only capture a single snap-shot of a protein’s structural conformation. However, inside a cell, where it is hard to routinely look, targets are dynamic entities, with druggable pockets coming and going all the time for discovery and potential exploitation. 

PROTEINi® (Protein-interference) is a live-cell assay system that probes for these hidden, or cryptic, druggable sites accross the whole human genome and simultaneously reveals those with a useful therapeutic function by registering a specific cellular response (or ‘phenotype’). 

At the heart of PROTEINi lies the use of protein-fragment libraries, harbouring billions of different 3-dimensional shapes, to enable saturation level functional probing of target protein conformations for new druggable space.  One library in particular (called a 'Phylomer' library) from our key partner Phylogica Ltd, is comprised of coding sequence fragments from a diverse array of bacteria and has demonstrated remarkably high functional hit rates in mammalian phenotypic assays (see example review by PM Watt in Nature Biotech 24(2) 2006).  

The SITESEEKER® platform uses these functionally validated protein fragments to then rapidly inform the design of small molecule drugs with the same shape, providing a continuous pipeline of highly validated first-in-class drug discovery programmes for out-licensing to Pharma.