title: A click chemistry approach to pleuromutilin conjugates with nucleosides or acyclic nucleoside derivatives and their binding to the bacterial ribosome.
abstract: Pleuromutilin and its derivatives are antibacterial drugs that inhibit protein synthesis in bacteria by binding to ribosomes. To promote rational design of pleuromutilin based drugs, 19 pleuromutilin conjugates with different nucleoside fragments as side chain extensions were synthesized by a click chemistry protocol. Binding was assessed by chemical footprinting of nucleotide U2506 in 23S rRNA, and all conjugates bind to varying degree reflecting their binding affinity to the peptidyl transferase center. The side chain extensions also show various protections at position U2585. Docking studies of the conjugates with the highest affinities support the conclusion that despite the various conjugations, the pleuomutilin skeleton binds in the same binding pocket. The conjugated triazole moiety is well accommodated, and the nucleobases are placed in different pockets in the 50S ribosomal subunit. The derivative showing the highest affinity and a significantly better binding than pleuromutilin itself contains an adenine-9-ylpropylene triazole conjugate to pleuromutilin C-22.
authors.affiliation: Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Lolk
authors.forename: Jacob
authors.initials: J
authors.lastname: Pøhlsgaard
authors.forename: Anne Sofie
authors.initials: AS
authors.lastname: Jepsen
authors.forename: Lykke H
authors.initials: LH
authors.lastname: Hansen
authors.forename: Henrik
authors.initials: H
authors.lastname: Nielsen
authors.forename: Signe I
authors.initials: SI
authors.lastname: Steffansen
authors.forename: Laura
authors.initials: L
authors.lastname: Sparving
authors.forename: Annette B
authors.initials: AB
authors.lastname: Nielsen
authors.forename: Birte
authors.initials: B
authors.lastname: Vester
authors.forename: Poul
authors.initials: P
authors.lastname: Nielsen
mesh_terms: D001419:Bacteria / Q000648:ultrastructure; D002621:Chemistry / Q000379:methods; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry* / Q000378:metabolism; D010458:Peptidyl Transferases / Q000378:metabolism; D011083:Polycyclic Compounds; D011485:Protein Binding; D012270:Ribosomes / Q000378:metabolism*; D000097567:Pleuromutilins
chemical_list: D004224:Diterpenes; D009705:Nucleosides; D010458:Peptidyl Transferases; D011083:Polycyclic Compounds; D000097567:Pleuromutilins; C014224:tiamulin