Enhanced RNA binding of dimerized aminoglycosides

Aminoglycoside antibiotics have recently emerged as an intriguing family of RNA binding molecules and they became leading structures for the design of novel RNA ligands. The demystification of the aminoglycoside-RNA recogniti on phenomenon is required for the development of superior binders. To explo re the existence of multiple binding sites in a large RNA molecule, we have synthesized covalently linked symmetrical and nonsymmetrical dimeric amino glycosides. These unnatural derivatives were compared to their natural "mon omeric" counterparts in their ability to inhibit the Tetrahymena ribozyme. The dimeric aminoglycosides inhibit ribozyme function 20 to 1.2 x 10(3) fol d more effectively than their natural parent compounds. The inhibition curv es of dimeric aminoglycosides have characteristic shapes suggesting the pre sence of at least two high affinity-binding sites within the ribozyme's thr ee-dimensional fold. The interaction of a dimeric aminoglycoside with two c omplementary sites of the RNA molecule is proposed. This binding motif may have implications on the development of new drugs targeting pivotal RNA mol ecules of bacterial and viral pathogens. (C) 1999 Elsevier Science Ltd. All rights reserved.