Abstract
RNA is increasingly recognized for its significant functions in biological systems and has recently become an important molecular target for therapeutics development. Aminoglycosides, a large class of clinically significant antibiotics, exert their biological functions by binding to prokaryotic ribosomal RNA (rRNA) and interfering with protein translation, resulting in bacterial cell death. They are also known to bind to viral mRNAs such as HIV-1 RRE and TAR. Consequently, aminoglycosides are accepted as the single most important model in understanding the principles that govern small molecule-RNA recognition, which is essential for the development of novel antibacterial, antiviral or even anti-oncogenic agents. This review outlines the chemical structures and mechanisms of molecular recognition and antibacterial activity of aminoglycosides and various aminoglycoside mimics that have recently been devised to improve biological efficacy, binding affinity and selectivity, or to circumvent bacterial resistance.
Highlights
RNA performs pivotal biological functions when organisms, including bacterial and viral pathogens, replicate
The modification provided an effective protection against aminoglycoside inactivation enzymes involved in aminoglycoside resistance, which represents a test case that a structure-based approach may be used to design ligands that maintain binding affinity to desired RNA targets but a poor substrate for enzymes that lead to inactivation
It has been generally believed that the intrinsic flexibility of RNA structures makes the structure-based rational drug design approach, which resulted tremendous success in protein-targeting therapeutic development, less suitable unless the target RNA is locked into a rigid conformation, which is not the case for most mRNAs
Summary
RNA performs pivotal biological functions when organisms, including bacterial and viral pathogens, replicate. When Hergenrother and coworkers prepared simple dimers of 2-DOS (5) by connecting two 2-DOS molecules with various aliphatic and aromatic linkers of different sizes, they were found to bind tightly to RNA hairpin loops of various sizes from 4 to 8 nucleotides, most of which contain 5’-GU-3’ sequence.[41] The dimers with the aromatic linkers exhibited slightly tighter binding over their aliphatic counterparts These examples show that novel RNA binding molecules may be built solely based on 2-DOS without the assistance of conjugated aminosugar(s), and the intrinsic RNA binding affinity of the 2-DOS may be useful targeting helical RNAs whose base pairing is disrupted, and RNAs of other types of secondary structure such as loops that conventional aminoglycosides do not bind. Wengel and coworkers introduced substituents aminosugar mimics oligomers of sugar diaminoacid (SDAs)
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