Molecular recognition of double-stranded RNA (dsRNA) represents an appealing goal for practical applications in biotechnology. Compared to dsDNA, there is much less known about binding preferences for dsRNA. Recent research developments have shown that peptide nucleic acids (PNA) bind in triple helical mode to dsRNA rich in homopurine tracts under physiologically relevant conditions. In an effort to prepare PNA capable of recognizing any RNA base pair of interest, we have undertaken a project aimed at rational design, synthesis, and binding studies of novel nucleoside bases capable of Hoogsteen hydrogen-bonding interactions with a Watson-Crick base pair of interest. In particular, given the known stability of the U*A-U triplet, we rationalized that an isoorotic acid derivative with a pendant heterocylic base capable of donating a hydrogen bond to the Uracil residue might form a tighter (and thus more selective) triplet.<br/>First, the rational design of nucleobases was undertaken by docking the Watson-Crick A-U base pair with novel nucleobases through Hoogsteen binding interactions. Using semi-empirical methods, computed energies of binding and hydrogen bonding distances have revealed several possible synthetic targets. In particular, amide and ester derivatives of isoorotic acid appear as reasonable targets. In turn, we have begun to synthesize a small library of isoorotic acid esters and amides capable of hydrogen bonding with the A-U base pair. Future work will include <sup>1</sup>H NMR complexation studies to experimentally determine binding affinities. Herein are presented our current results of computations, synthetic efforts, and binding studies. It is noteworthy that this work was a result of a collaborative class project for Chemistry 455/456.

Design, synthesis, and binding of novel nucleobases for incorporation into peptide nucleic acids

251st National Meeting (2016)

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