Extreme Diversity™ Platform

Our Extreme Diversity™ Platform

The Extreme Diversity™ platform, a proprietary macrocyclic peptide chemistry technology from Ra Pharma®, produces synthetic macrocyclic peptides that combines the diversity and specificity of antibodies with the pharmacological properties of small molecules, with the following advantages:

  • High Affinity and Potency — Ra Pharma’s peptides are cyclic, and therefore conformationally rigid, thereby “locking” the molecule in the conformation in which it binds optimally to its target and leading to affinity and potency similar to antibodies.
  • High Specificity — Our peptides are larger than most drugs taken in pill form, allowing them to have more contact points when bound to their targets, thus affording similar specificity as antibodies.
  • Novel Mechanisms of Interaction — The use of non-natural amino acids with new chemical functionalities expands the manner in which peptides can interact with target proteins, opening up the possibility for new mechanisms to modulate protein function in the body.
  • High Stability — The backbone modification and relatively rigid, cyclic structure of our peptides are designed to reduce degradation. As a result, we believe our peptides will have higher stability in the body than natural peptides. Further, they will not denature or unfold over time, and have higher stability than antibodies and biologics, potentially allowing for room temperature storage over the entire distribution chain.
  • Improved Bioavailability — The relatively small size of our peptides allows them to enter the circulation readily when administered by a variety of potential routes, including subcutaneous injection or oral administration, an advantage over many monoclonal antibody and biologic therapies which require intravenous infusion.
  • Half-life Modification — As synthetic products, we can readily modify their cyclic peptides with chemical groups that modify the circulating half-life in the body, including lipids, carbohydrates, and polymers such as polyethylene glycol, providing the potential to optimize dosing by fine-tuning the pharmacokinetic properties.
  • Reduced Safety Risks — Unlike antibodies and biologics, our peptides are completely synthetic, eliminating the potential for vial and cellular protein contamination that adds risk to therapeutics produced in mammalian cells.
  • Favorable Manufacturing Processes and Costs — As synthetic products, our peptides do not need complex fermentation facilities, allowing their production to be easily sourced from multiple vendors at lower costs than mammalian cell products. We are driving the development of the next generation of orally-available drugs. Certain cyclic peptides are being developed into orally-available drugs, as exemplified by the Company’s high-value target developed in collaboration with Merck. We can also use this platform to develop novel macrocycle peptides to guide the development of orally-available, traditional small molecule drugs such as our oral C5 inhibitors.

Ra Pharma utilizes a process called “mRNA display” to produce extremely large and diverse libraries of peptides from which to screen for potential product candidates.

mRNA Display Graphic

Step 1 — creating of peptide-mRNA fusion libraries: mRNA is translated into peptides by ribosomes using both naturally occurring amino acids and non-natural amino acids. The antibiotic puromycan is linked to each mRNA to create peptide-mRNA fusions. As a result, the translation of a relatively small amount of mRNA results in a large and diverse library of up to 100 trillion peptide-mRNA fusions.

Step 2 — creating rigid macrocycle peptides: The peptide-mRNA display libraries are then modified chemically to link two specific amino acids together and cyclize the peptide into rigid macrocycle peptides. In addition, the mRNA components of the fusions are converted to cDNA (a hybrid of mRNA and DNA) at this step.

Step 3 — selecting target peptides: Once a cyclic peptide mRNA display library is prepared, the Company selects peptides that bind to the desired target protein immobilized on the surface of a small, solid bead.

Step 4 — DNA amplification: After an initial set of peptides that bind to the target protein are selected, the Company leverages the mRNA to amplify the peptides’ corresponding DNA via a DNA amplifying technique called Polymerase Chain Reaction, or PCR.

Steps 5, 6 and 7 — repeat process to select lead candidate: The cycle can be repeated to enrich for candidate peptides (Step 5), the DNA’s sequence is determined and desired peptide candidates are synthesized based on the information in its corresponding DNA (Step 6), and candidate peptides are further screened and optimized for desired targeted binding affinity to select a lead candidate (Step 7).

Steps 5, 6 and 7 — repeat process to select lead candidate: The cycle can be repeated to enrich for candidate peptides (Step 5), the DNA’s sequence is determined and desired peptide candidates are synthesized based on the information in its corresponding DNA (Step 6), and candidate peptides are further screened and optimized for desired targeted binding affinity to select a lead candidate (Step 7).

Steps 5, 6 and 7 — repeat process to select lead candidate: The cycle can be repeated to enrich for candidate peptides (Step 5), the DNA’s sequence is determined and desired peptide candidates are synthesized based on the information in its corresponding DNA (Step 6), and candidate peptides are further screened and optimized for desired targeted binding affinity to select a lead candidate (Step 7).

  • Step 1 — creating peptide-mRNA fusion libraries: mRNA is translated into peptides by ribosomes using both naturally occurring amino acids and non-natural amino acids. The antibiotic puromycin is linked to each mRNA to create peptide-mRNA fusions. As a result, the translation of a relatively small amount of mRNA results in a large and diverse library of up to 100 trillion peptide-mRNA fusions.
  • Step 2 — creating rigid macrocycle peptides: The peptide-mRNA display libraries are then modified chemically to link two specific amino acids together and cyclize the peptide into rigid macrocycle. In addition, the mRNA components of the fusions are converted to cDNA (a duplex of mRNA and DNA) at this step.
  • Step 3 — selecting target peptides: Once a cyclic peptide mRNA display library is prepared, the Company selects peptides that bind to the desired target protein immobilized on the surface of a small, solid bead.
  • Step 4 — DNA amplification: After an initial set of peptides that bind to the target protein are selected, we leverage the mRNA to amplify the peptides’ corresponding DNA via a DNA amplifying technique called Polymerase Chain Reaction, or PCR.
  • Steps 5, 6 and 7 — repeat process to select lead candidate: The cycle can be repeated to enrich for candidate peptides (Step 5). Ultimately, the DNA’s sequence is determined and desired peptide candidates are synthesized based on the information in its corresponding DNA (Step 6), and candidate peptides are further screened and optimized for desired targeted binding affinity to select a lead candidate (Step 7).