Design, synthesis and ribosome binding of chloramphenicol nucleotide and intercalator conjugates.
Molecular modelling based on X-ray structures of the antibiotic drug chloramphenicol bound in a bacterial ribosome has been used for design of chloramphenicol derivatives. Conjugates of the chloramphenicol amine through appropriate linkers to either a pyrene moiety or to a mono- or dinucleotide moiety were designed to improve binding to ribosomes by providing specific interactions in the peptidyl transferase site or to the P-loop in the ribosome. Specific binding of the conjugates were investigated by footprinting analysis using chemical modifications of accessible nucleotides in ribosomal RNA. The pyrene chloramphenicol conjugate shows enhanced binding to the chloramphenicol binding site compared to the native chloramphenicol, whereas the four nucleotide conjugates could not be shown to bind to the chloramphenicol binding site or to the P-loop.
Johansson
Dorte
D
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, 5230 Odense M, Denmark.
Jessen
Carsten H
CH
Pøhlsgaard
Jacob
J
Jensen
Kenneth B
KB
Vester
Birte
B
Pedersen
Erik B
EB
Nielsen
Poul
P
D001665:Binding Sites; D002701:Chloramphenicol / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*
D007364:Intercalating Agents; D009711:Nucleotides; D009943:Organophosphorus Compounds; C434331:phosphoramidite; D002701:Chloramphenicol