Design, synthesis and binding properties of the chiral peptide nucleic acid $(\gamma^{3}-PNA)$

Abstract

PNA is a class of artificial nucleic acid that has neutral amide backbone, which endowed PNA with outstanding properties such as chemical/biological stability and higher binding affinity to both DNA and RNA. However, no binding selectivity between PNA/RNA and PNA/DNA was observed, which may cause potential side effects for antisense application. Furthermore, the similar binding affinity between parallel and antiparallel orientation presumably due to its achiral backbone would be also problematic. There have been several efforts to overcome the drawbacks by modifying PNA backbone scaffold, but few examples are successful. We have developed new chiral peptide nucleic acid based on gamma-peptide scaffold, which binds RNA more specifically as well as in an antiparallel fashion. Efficient synthetic protocol for $\gamma^{3}-PNA$ monomers is also developed. The RNA binding specificity was assessed by using Tm measurement and $\gamma^{3}-PNA$ chip-based assay. Introduction of one or two $\gamma^{3}-PNA$ monomers into aeg-PNA skeleton could restore the helical propensity of the PNA oligomer, whereas the aeg-PNA is unstructured by CD analysis. In addition, we successfully synthesized homo $\gamma^{3}-PNA$ oligomers and confirmed the binding characteristics of them.