PepMetics®: Our Engine for Paradigm Shifts on PPI Drug Discovery

Science has solved numerous issues relating to disease treatment through the discovery of new drugs. Small synthetic molecules, natural products, antibodies, and nucleic acids have been developed into candidates through the aid of SBDD (structure-based drug design) and HTS (high-throughput screening) approaches. Tremendous efforts have been thrown into molecular target drugs, but about 85% of promising disease targets are as yet considered undruggable.

As a player in pharmaceuticals, finding cures for the incurable is a huge proposition. Thus, we are aiming for a paradigm shift that transforms the “undruggable” into a reasonably “druggable” target through the use of our unique and invaluable technology – PepMetics®.

PepMetics® Technology is our proprietary drug discovery platform that empowers a molecule to mimic nature. Metabolism is mostly controlled by interaction of biomolecules like proteins and DNA/RNA. Nature has developed incredibly selective interactions with high affinity.

PPI (protein-protein interaction) is a representative interaction deeply related to a broad range of diseases. Our approach is to mimic a crucial peptide or amino acid sequence to achieve selective PPI control by PepMetics® molecules. We do not use a peptide itself, but rather a small molecule with 3 to 5 substituents like an amino acid side chain. Needless to say, the substituents of PepMetics® molecules can be more easily modified, enabling high-speed lead optimization through both conventional and novel medchem technology.

PepMetics® Molecules were originally designed to mimic a-helix or b-turn peptides by our stable scaffolds with reasonably restricted conformational changes. PepMetics® is distinguished peptide mimetics because our molecule mimics multiple surfaces of a structured peptide. It resembles “one-turn” of an a-helix. Conventional peptide mimetics mostly mimic just one side of a helix, which limits the “Nature mimicry” approach for drug discovery. PepMetics® molecules have the potential to achieve three-dimensional mimicry of a peptide or a small portion of a protein.

PepMetics® molecules are synthetized by a combinatorial chemistry approach. Three to 5 substituents are combined by simple units so as to quickly prepare the scaffolds with attractive substituents. We have already developed more than 30 scaffolds to mimic peptides, a-helices, and b-turns. It is still expanding and opening more chances to reach undruggable targets.

Furthermore, these molecules can be readily chemically modified to optimize their structure for PPI or other potential interactions. PepMetics® has the same degree of synthetic flexibility as conventional small molecules, if not more, and yet is an outstanding opportunity for drug discovery targeting PPI.

We would also like mention that PepMetics® molecules have interesting, sp3-rich scaffolds that makes them more promising for drug development. Principal component analysis has shown that PepMetics® molecules are more like natural product drugs and natural product-derived, approved drugs. They are distinct from conventionally screened library compounds, which have plain-like structures and less resembles three-dimensional natural products.

Through the chemist’s eyes, PepMetics® molecules’ structural features as well as the synthetic flexibility similar to conventional small molecules may seem impressive. We believe these characteristics enables us to approach undruggable targets that could lead to cures for diseases.

Through partnerships with Eisai and Ohara Pharmaceuticals, PepMetics® molecules are currently being used in clinical trials targeting CBP-b-catenin interaction. We have already discovered elf4E-elf4G1 PPI is also be suppressed by our original PepMetics® molecules. We are currently calling for a partner to share in the opportunity to develop a new cancer treatment.

The potential of PepMetics® molecules is expanding. In collaborations with both academia and science companies, PepMetics® molecules have been shown to possess the potential to target IDP (intrinsically disordered proteins). It has also been revealed to challenge sequence mimetics, which means a protein without a solved structure would become a druggable target.

Binding structure with reasonable resolution is essential for the conventional SBDD approach. However, utilizing a sequence mimetics approach enables us to predict probable hit compounds. Our molecule would give an opportunity to discover a lead compound with minimal efforts on screening assays.

To aid in the acceleration of drug discovery, we have already established the PepMetics® Library. The PepMetics® Library consists of more than 20 thousand PepMetics® molecules, covering a variety of amino acid side chains and non-natural, synthetic substituents. This is a powerful tool for screening as PepMetics® molecules have different characteristics than conventional small-molecule libraries.

Up to 250 million or more PepMetics® molecules can be screened. We would like to say that there are virtually infinite number of compounds can be synthesized with medchem approach.

Our concept for the PepMetics® Library is three-layered. The first layer, the real library, is the stocked library that instantaneously goes for first screening. The second layer, the on-demand library, consists of readily synthesized molecules prepared using our stocked intermediates. Judging from the results of first screening or investigations in silico, we can quickly prepare a set of molecules of interest. The on-demand library is ever-expanding and currently has a more than 200-molecule capability. The third layer, the virtual library, is the preparable sets of PepMetics® molecules made with our combinatorial approach. We have the capability to screen at least 250 million formulations, and even greater opportunities would be found through in silico approaches.

Recently, we launched multi-project drug discovery collaboration with Roche and Genentech, providing a set of PepMetics® molecules from our library. We would like to encourage you to work with us to overcome the challenge of undruggable targets with our PepMetics® library. The PPI approach is becoming more and more established, and PepMetics® molecules, with their unique three-dimensional structure, can give you the opportunity to start a paradigm shift in drug discovery.

We are always searching for partners in our pursuit of novel drug discovery and medical developments. In addition, PRISM is open to any level of scientific discussions. Join us to enter a new world of novel drug discovery through the use of PepMetics® that we whole will lead to the relief and recovery of all people suffering from illness.

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