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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\u2010through point\u2010mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A\u2010site leads to negligible affinity for most AGs. Herein we report the synthesis of 6\u2032\u2010fluorosisomicin, the first 6\u2032\u2010fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A\u2010site, but not the bacterial A\u2010site, as evidenced by X\u2010ray co\u2010crystal structures. The respective dispositions of 6\u2032\u2010fluorosisomicin within the bacterial and protozoal A\u2010sites reveal that the fluorine atom acts only as a hydrogen\u2010bond acceptor to favorably interact with G1408 of the protozoal A\u2010site. Unlike aminoglycosides containing a 6\u2032\u2010ammonium group, 6\u2032\u2010fluorosisomicin cannot participate in the hydrogen\u2010bonding pattern that characterizes stable pseudo\u2010base\u2010pairs with A1408 of the bacterial A\u2010sites. 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.<\/jats:p>","DOI":"10.1002\/cmdc.201800166","type":"journal-article","created":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T02:00:41Z","timestamp":1526436041000},"page":"1541-1548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structure\u2010Based Design of a Eukaryote\u2010Selective Antiprotozoal Fluorinated Aminoglycoside"],"prefix":"10.1002","volume":"13","author":[{"given":"Hiroki","family":"Kanazawa","sequence":"first","affiliation":[{"name":"Graduate School of Science and Technology Sophia University  7-1 Kioi-cho, Chiyoda-ku 102-8554 Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar M.","family":"Saavedra","sequence":"additional","affiliation":[{"name":"Department of Chemistry Universit\u00e9 de Montr\u00e9al  C.P. 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