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Differential Selectivity of Natural and Synthetic Aminoglycosides towards the Eukaryotic and Prokaryotic Decoding A Sites
Author(s) -
Kondo Jiro,
Hainrichson Mariana,
Nudelman Igor,
ShallomShezifi Dalia,
Barbieri Christopher M.,
Pilch Daniel S.,
Westhof Eric,
Baasov Timor
Publication year - 2007
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.200700271
Subject(s) - aminoglycoside , antibiotics , selectivity , computational biology , chemistry , biology , biochemistry , catalysis
The lack of absolute prokaryotic selectivity of natural antibiotics is widespread and is a significant clinical problem. The use of this disadvantage of aminoglycoside antibiotics for the possible treatment of human genetic diseases is extremely challenging. Here, we have used a combination of biochemical and structural analysis to compare and contrast the molecular mechanisms of action and the structure–activity relationships of a new synthetic aminoglycoside, NB33, and a structurally similar natural aminoglycoside apramycin. The data presented herein demonstrate the general molecular principles that determine the decreased selectivity of apramycin for the prokaryotic decoding site, and the increased selectivity of NB33 for the eukaryotic decoding site. These results are therefore extremely beneficial for further research on both the design of new aminoglycoside‐based antibiotics with diminished deleterious effects on humans, as well as the design of new aminoglycoside‐based structures that selectively target the eukaryotic ribosome.