Whether aminoglycoside-induced base destacking, or other factor(s

Whether aminoglycoside-induced base destacking, or other factor(s) governing the energetics and dynamics are associated such with aminoglycoside-induced read-through at the human rRNA-A site, is not clear and requires further study. Recently, Westhof et al. (35, 36) and Hermann et al. (19) have reported the X-ray structures of the native conformation of human cytoplasmic rRNA-A site and its complex with the aminoglycoside apramycin. Two different conformations of the free cytoplasmic A site were reported that corresponded with its ��on�� state, with the two adenine residues A1492 and A1493 fully extruding, and its ��off�� state, with A1491 fully extruded and A1493 partially extruded (36).

These findings suggest that the aminoglycoside apramycin specifically binds and stabilizes the nondecoding off state of the cytoplasmic A site, thereby inhibiting translocation of the eukaryotic ribosome rather than disturbing decoding fidelity as in prokaryotes (19, 35, 37). Importantly, there are still no structures of the human A-site in the complex with any of the aminoglycosides that induce read-through. Despite their ability to induce ribosomal read-through, the known nephrotoxic and ototoxic complications of aminoglycosides limit the use of this class of drugs therapeutically in patients with PSC mutations (43). The origin of this toxicity is multifactorial, including but not limited to interactions with phospholipids, inhibition of phospholipases, formation of free radicals, and binding to both the eukaryotic ribosomal A-site and mitochondrial 12S rRNA A-site.

To limit the toxicity, various approaches are being attempted including 1) the use of antioxidants to reduce free radical levels (31, 51); 2) the use of poly-l-aspartate (4, 13) and daptomycin (55, 56) to reduce the ability of aminoglycosides to interact with phospholipids; 3) the administration of agonists that compete for aminoglycoside binding to megalin (61); and 4) structural modifications that limit toxicity without altering the efficacy of PSC read-through (45) and the isolation of a nonnephrotoxic aminoglycoside (gentamicin) congener (49). Whether any of these approaches will turn out in the long run to be accepted is currently unknown. Patients with NBCe1-A mutations are known to have band keratopathy, cataracts, and glaucoma. The eye phenotype can potentially be debilitating and lead to blindness (11, 20, 21, 25�C27).

Of interest is the finding that the Q29X mutation. which is selective for NBCe1-A (sparing Drug_discovery NBCe1-B and NBCe1-C), does not result in cataracts or band keratopathy as do mutations that effect all variants (26). The latter may be due to differences in the expression of NBCe1 variants in various regions of the eye (8, 57). In general, the eye appears a priori to be an easier target for drug therapy than the kidney.

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