A click chemistry approach to pleuromutilin conjugates with nucleosides or acyclic nucleoside derivatives and their binding to the bacterial ribosome.
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.
Lolk
Line
L
Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, 5230 Odense M, Denmark.
Pøhlsgaard
Jacob
J
Jepsen
Anne Sofie
AS
Hansen
Lykke H
LH
Nielsen
Henrik
H
Steffansen
Signe I
SI
Sparving
Laura
L
Nielsen
Annette B
AB
Vester
Birte
B
Nielsen
Poul
P
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
D004224:Diterpenes; D009705:Nucleosides; D010458:Peptidyl Transferases; D011083:Polycyclic Compounds; D000097567:Pleuromutilins; C014224:tiamulin