Peptide Nucleic Acids (PNAs) are synthetic molecules that mimic deoxyribonucleic acid (DNA). Developed in the early 1990s, these oligomers preserve base-specific pairing (A and T, C and G), but the phosphodiester backbone is replaced with a polyamide structure that is “peptide-like” in that it contains a peptide bond, but is not readily susceptible to nuclease or protease degradation.
PNAs have long been appreciated for their properties of:
Stability in serum and cell extracts
Resistance to nuclease and protease digestion
Higher affinity for DNA and RNA compared to oligonucleotide analogs
Less tolerance to base pair mismatches
However, early PNAs proved not to have suitable physicochemical properties for therapeutic drug development.
Breakthrough PNA chemistry: exclusive IP
A significant breakthrough occurred when chemists at Carnegie Mellon University modified the side chains of classic PNAs at the gamma carbon with PEG (polyethylene glycol) leading to improved solubility, stability, and binding affinity.
Gamma mini-PEG PNA
In addition to the improvements in solubility, stability, and binding affinity, the gamma substitution was also found to enforce a helical pre-organization to these oligos that markedly enhanced binding affinity for the DNA target. The resultant novel backbone allows for stronger hybridization with complementary nucleic acids. This work further demonstrated that miniPEG γPNAs were capable of invading mixed sequence double helical B-DNA through Watson-Crick base pairing. This advance in PNA chemistry created an entirely new class of oligomers and chemical space with therapeutic potential.
Triplex formation creates an altered helical structure that is recognized by endogenous DNA repair factors and can induce recombination of a single-stranded donor DNA encoding a desired modification at a nearby genomic location. The ability of PNAs to induce recombination comes directly from their ability to tightly bind to DNA at their designated sites. Because they do not possess any direct nuclease activity, their safety profile is substantially increased.
We have licensed exclusive worldwide rights to this chemistry and we continue to expand on this intellectual property foundation. Our innovative chemistry enables single stranded PNAs to bind double stranded DNA with high specificity and affinity via hydrogen binding and form triplexes at the site of binding. Depending on their design, our PNAs are capable of modulating DNA behavior in a number of ways, including promotion of high-fidelity gene repair both ex vivo and in vivo.
FDA approval for marketing depends not only upon safety and efficacy but also upon the ability to manufacture with consistency and reproducibility. The components of our drug product are chemically synthesized, free of biologics, and can therefore more easily be reproducibly manufactured and characterized using well-established analytical methods.