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Four new isoorotamide (Io)-containing PNA nucleobases have been designed for A-U recognition of double helical RNA. New PNA monomers were prepared efficiently and incorporated into PNA nonamers for binding A-U in a PNA:RNA 2 triplex. Isothermal titration calorimetry and UV thermal melting experiments revealed slightly improved binding affinity for singly modified PNA compared to known A-binding nucleobases. Molecular dynamics simulations provided further insights into binding of Io bases in the triple helix. Together, the data revealed interesting insights into binding modes including the notion that three Hoogsteen hydrogen bonds are unnecessary for strong selective binding of an extended nucleobase. Cationic monomer Io8 additionally gave the highest affinity observed for an A-binding nucleobase to date. These results will help inform future nucleobase design toward the goal of recognizing any sequence of double helical RNA., (© 2023 Wiley-VCH GmbH.)