Recognition of Triple Helical Nucleic Acids by Aminoglycosides

Abstract

Aminoglycosides, traditional RNA binders, were found to be a new class of triple helical nucleic acid-stabilizing ligands. Neomycin, of all the aminoglycosides, has shown the most significant effects in stabilizing DNA, RNA, and hybrid triple helices. When compared with minor groove binders or intercalators, neomycin excels at triple helical stabilization in most cases. Molecular modeling studies suggest that neomycin reaches into the larger Watson-Hoogsteen groove. The charge and shape complementarity are the key factors in neomycin-triplex recognition. By conjugating neomycin with intercalators such as BQQ (a potent triple helix intercalating agent designed by Hélène), we have progressed in developing more potent triple helix stabilizing ligands. The design of such dual or even triple recognition ligands opens a new paradigm for recognition of triple helix nucleic acids. The article herein presents studies of neomycin as the first molecule that can selectively stabilize nucleic acid triplex structures. These studies are supported by our recent discovery that neomycin prefers to bind to A-like conformations, of which triple helix structures are known to display some characteristics. These findings will contribute to the development of a new series of triplex-specific ligands, and may contribute to either antisense or antigene therapies.