Designed spiro-bicyclic analogues targeting the ribosomal decoding center

The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.Mimicking aminoglycosides: An optimized approach has been developed for the synthesis of rigid 5,6-, 6,6- and 7,6-bicyclic scaffolds that mimic many of the interactions of the natural aminoglycosides for the ribosomal decoding center. Their binding affinities for the A-site along with their potential to inhibit protein production in vitro are presented. Our results comprise useful SAR observations for structure-based drug design specific for RNA constructs.