Structure-Based Design of a Eukaryote-Selective Antiprotozoal Fluorinated Aminoglycoside.

Autor: Kanazawa H; Graduate School of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku, 102-8554, Tokyo, Japan., Saavedra OM; Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, Canada., Maianti JP; Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, Canada., Young SA; Biomedical Sciences Research Complex, University of St. Andrews, St. Andrews, Fife, Scotland, KY16 9ST, UK., Izquierdo L; ISGlobal, Hospital-Clinic-Universitat de Barcelona, Barcelona, Spain., Smith TK; Biomedical Sciences Research Complex, University of St. Andrews, St. Andrews, Fife, Scotland, KY16 9ST, UK., Hanessian S; Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, H3C 3J7, Canada., Kondo J; Graduate School of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku, 102-8554, Tokyo, Japan.; Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku, 102-8554, Tokyo, Japan.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2018 Aug 10; Vol. 13 (15), pp. 1541-1548. Date of Electronic Publication: 2018 Jul 04.
DOI: 10.1002/cmdc.201800166
Abstrakt: Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6'-fluorosisomicin, the first 6'-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A-site, as evidenced by X-ray co-crystal structures. The respective dispositions of 6'-fluorosisomicin within the bacterial and protozoal A-sites reveal that the fluorine atom acts only as a hydrogen-bond acceptor to favorably interact with G1408 of the protozoal A-site. Unlike aminoglycosides containing a 6'-ammonium group, 6'-fluorosisomicin cannot participate in the hydrogen-bonding pattern that characterizes stable pseudo-base-pairs with A1408 of the bacterial A-sites. Based on these structural observations it may be possible to shift the biological activity of aminoglycosides to act preferentially as antiprotozoal agents. These findings expand the repertoire of small molecules targeting the eukaryotic ribosome and demonstrate the usefulness of fluorine as a design element.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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