Development of stimuli responsible water-soluble functional polymers for biomedical purpose: Creating ischemia cell specific oligonucleotide therapeutics system with environment-responsive peptide ribonucleic acids (PRNAs)

We have reported a series of novel artificial nucleic acids, named Peptide Ribonucleic Acids (PRNAs), as promising candidates for ischemic/hypoxic cell specific oligonucleotide therapeutics. PRNAs are consisted with γ- and/or α-glutamate peptide backbone and 5′-amino ribonucleoside moiety in the side chain. For applying ischemic/hypoxic cell specificificity, PRNAs containing phenylboronic acid moiety with appropriate substients (PRNA-PBA) were synthesized. Under the normal cellular condition (pH = 7.2), the PRNA-PBA unit forms intramolecular cyclic borate ester with 2:3′-cis-diole of PRNA's furanose residue, and then PRNA's nucleobase preferres syn orientation, which is no recognition/complexation ability with any nucleobases of RNA and/or DNA. On the other hand, under the ischemic/hypoxic cellular conditions (pH 6.2 ∼ 5.8), the pH triggered nucleobase-orientation switching of PRNA from syn to anti is induced by dissociation of the borate ester and then anti oriented nuclobases of PRNAs recognize and form stable complex with target functional RNA, which is an essential function of oligonucleotide therapeutics strategy. Therefore, PRNAs expect to be intracellular environment condition responsible artificial nucleic acids for oligonucleotide therapeutics strategy, and then can discriminate ischemic/hypoxic cells and normal cell.