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Designed Spiro‐Bicyclic Analogues Targeting the Ribosomal Decoding Center
Author(s) -
Cottin Thomas,
Pyrkotis Constantina,
Stathakis Christos I.,
Mavridis Ioannis,
Katsoulis Ioannis A.,
Anastasopoulou Panoula,
Kythreoti Georgia,
Zografos Alexandros L.,
Nahmias Victoria R.,
Papakyriakou Athanasios,
Vourloumis Dionisios
Publication year - 2011
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201000591
Subject(s) - ribosome , rna , rational design , computational biology , synthetic biology , ribosomal rna , translation (biology) , protein biosynthesis , chemistry , combinatorial chemistry , transfer rna , drug design , bicyclic molecule , stereochemistry , biology , biochemistry , messenger rna , genetics , gene
Abstract 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.