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Aminoglycoside derivatives and mimetics as RNA binders

Abstract

Ribonucleic acids (RNAs) are functionally sophisticated molecules that play key roles in essential biological processes such as protein biosynthesis, splicing, transcriptional regulation and retroviral replication. Due to the functional diversity of these molecules, a considerable amount of attention has been focused on developing RNA-targeting therapeutics. Aminoglycoside antibiotics are a family of structurally related natural products that have been found to bind and modulate the function of a variety of therapeutically significant RNA targets, including 16S ribosomal RNA, tRNA, HIV RRE and Tar RNAs, and group I introns. The target promiscuity of the aminoglycosides is likely due to their electrostatically driven binding mode and their conformational adaptability. To study the role of the conformational flexibility of aminoglycosides in RNA binding and to improve the aminoglycosides RNA specificity, a type of novel conformationally constrained aminoglycoside derivatives designed to specifically targeting ribosomal A-site RNA were synthesized. In addition, a series of beta-cyclohexyl peptides aminoglycoside mimics were designed, which, with improved rigidity and established peptide chemistry, are suitable for screening RNA binders with high RNA specifies. In pursuance of this objective, a variety of beta-amino acid building blocks were synthesized

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