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Delivering on the Untapped Potential of Peptides

Functionally dense and structurally diverse, peptides represent an extraordinarily valuable class of molecules for performing complex functions. Poor oral bioavailability presently limits peptides to delivery by injection. Chemists have traditionally needed to replace certain features of peptides with peptide-like or “peptidomimetic” features to enhance bioavailability. This approach is time- and resource-intensive and usually fails at delivering high quality clinical leads. Ra scientists have devised an efficient route to produce and screen massive peptidomimetic libraries, opening the door to direct selection of drug-like, cell-permeable molecules from complex pools. The resulting products, Cyclomimetics™, have clinical utility as oral alternatives for currently marketed injectable biologics, as well as for addressing previously “undruggable” targets, such as intracellular protein-protein interactions.

Extreme Diversity™ Libraries and Selection Platform

Peptide modifications aimed at enhancing bioavailability have historically been added after a candidate sequence is isolated, often reducing potency and usually failing to generate high quality clinical leads. Ra’s Extreme Diversity™ platform encompasses a complete set of tools for drug discovery. Ra uses in vitro display technologies to create libraries of up to 100 trillion drug-like molecules and directly select extremely rare compounds with desirable features. With the Extreme Diversity™ platform, Ra is able to incorporate synthetic, non-natural amino acids while the library is being created, enabling a much more efficient process for identifying lead molecules. Through this approach, Ra can rapidly generate and select high affinity molecules with drug-like properties, completing the discovery and optimization stages in a matter of weeks, while avoiding the failures experienced by medicinal chemists seeking to modify candidate sequences.

The Company’s libraries are comprised of Cyclomimetics™: small, cyclic, peptide-like polymers with backbone and side-chain modifications that provide unique, beneficial properties not found in natural peptides. The small size results in a low risk of immunogenicity due to poor MHC presentation, while the structural modifications are known to increase cell permeability, stability, potency, and bioavailability.

Development Portfolio

Ra is initially focusing on difficult to target protein-protein interactions in areas that have not been successfully addressed with other technologies, including cancer, inflammation and autoimmune disease, diabetes, cardiovascular disease, and ophthalmology. Ra is also leveraging its transformational technology to provide orally available products to replace injectable biologics for a range of common and rare diseases.

References

Ma, Z., and Hartman, M.C. (2012). In Vitro Selection of Unnatural Cyclic Peptide Libraries via mRNA Display. In J.A. Douthwaite & R.H. Jackson (Eds.), Ribosome Display and Related Technologies: Methods and Protocols (pp. 367-390). Springer New York.

Josephson, K., Hartman, M.C., and Szostak, J.W. (2005). Ribosomal synthesis of unnatural peptides. J. Am. Chem. Soc. 127(33):11727-11725.

Forster, A.C., Tan, Z., Nalam, M.N., Lin, H., Qu, H., Cornish, V.W., and Blacklow, S.C. (2003). Programming peptidomimetic synthesis by translating genetic codes designed de novo. Proc. Natl. Acad. Sci. (USA). 100(11):6353-6357.

Freidinger, R.M. (2009). Using the ribosome to synthesize peptidomimetics. F1000 Biol. Rep. 1:53.