The selective recognition of RNA sequences and the ability to detect and inhibit function is a highly desirable goal for both fundamental research and practical applications in biotechnology that will likely uncover new discoveries of the functional importance of many RNA transcripts. Although anti-sense oligonucleotides target single-stranded RNA, many non-coding RNAs fold into double helical secondary structures that are challenging targets for molecular recognition. Recent research developments have shown that peptide nucleic acids (PNA) bind dsRNA through a triple helix in homopurine tracts under physiologically relevant conditions. Thymidine (T) is historically known to bind A-U, and more recently 2-aminopyridine (M) was demonstrated to bind selectively to G-C. Yet, binding of pyrimidines remains a challenge and there still exists no general method for the sequence selective recognition of any sequence of dsRNA.<br/> <br/>Our research involves addressing this shortcoming through the rational design of nucleobases for Hoogsteen binding of PNA to dsRNA. Guided by computational analysis, we have determined and begun syntheses on several potential targets for binding studies that retain key structural features of known nucleobases (e.g. T and M) that bind purines, and extending them with a linker and additional heterocycle that can recognize the pyrimidine. In addition, our design aims for planar systems with the ability to pi-stack in the triple helix. Finally, an important feature of the design is use of the same extended nucleobase for recognition of G-C and C-G base pairs and A-U and U-A base pairs. In doing so, we are in essence utilizing the strong binding of M and T bases to increase the binding affinity for the inverted base pair. This presentation will highlight both design and synthetic progress toward intended targets along with preliminary studies on PNA-RNA binding.<br/>           <br/>

Design and synthesis of pi-extended nucleobases for sequence selective triple-helical recognition of RNA using peptide nucleic acids

255th National Meeting (2018)

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