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Publication Abstract from PubMed

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'-fluoro sisomicin, 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'-F sisomicin within the bacterial and protozoal A-sites reveal that fluorine acts only as an H-bond acceptor to favorably interact with G1408 of the protozoal A-site. Unlike aminoglycosides containing a 6'-amino group, 6'-F sisomicin cannot participate in the H-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 antiprotozoals. These findings expand the repertoire of small-molecules targeting the eukaryotic ribosome and demonstrate the usefulness of fluorine as a design element.

Structure-Based Design of a Eukaryote-Selective Antiprotozoal Fluorinated Aminoglycoside.,Kanazawa H, Saavedra OM, Maianti JP, Young SA, Izquierdo L, Smith TK, Hanessian S, Kondo J ChemMedChem. 2018 May 15. doi: 10.1002/cmdc.201800166. PMID:29766661^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.