title: Designed spiro-bicyclic analogues targeting the ribosomal decoding center.
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.
authors.affiliation: Laboratory of Chemical Biology of Natural Products and Designed Molecules, Institute of Physical Chemistry, N.C.S.R. "Demokritos", 15310 Ag. Paraskevi Attikis, Athens, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cottin
authors.forename: Constantina
authors.initials: C
authors.lastname: Pyrkotis
authors.forename: Christos I
authors.initials: CI
authors.lastname: Stathakis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mavridis
authors.forename: Ioannis A
authors.initials: IA
authors.lastname: Katsoulis
authors.forename: Panoula
authors.initials: P
authors.lastname: Anastasopoulou
authors.forename: Georgia
authors.initials: G
authors.lastname: Kythreoti
authors.forename: Alexandros L
authors.initials: AL
authors.lastname: Zografos
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Nahmias
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papakyriakou
authors.forename: Dionisios
authors.initials: D
authors.lastname: Vourloumis
mesh_terms: D000475:Alkenes / Q000737:chemistry; D001483:Base Sequence; D015195:Drug Design; D006027:Glycosides / Q000737:chemistry; D006900:Hydroxylation; D007659:Ketones / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry; D012329:RNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity
chemical_list: D000475:Alkenes; D006027:Glycosides; D007659:Ketones; D009942:Organometallic Compounds; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D013141:Spiro Compounds