When proteins start to make sense: fine-tuning of aminoglycosides for PTC suppression therapy
Aminoglycosides (AGs) are highly potent antibacterial agents, which are known to exert their deleterious effects on bacterial cells by interfering with the translation process, leading to aberrant protein synthesis that usually results in cell death. Nearly 45 years ago, AGs were shown to induce read-through activity in prokaryotic systems by selectively encoding tRNA molecules at premature termination codon (PTC) positions. However, only in the last 20 years has this ability been demonstrated in eukaryotic systems, highlighting their potential as therapeutic agents to treat PTC induced genetic disorders. Despite the great potential, use of AGs in these applications is quite restricted due to relatively high toxicity values observed upon their administration. Over the last few years, several synthetic derivatives were developed to overcome some of the enhanced toxicity issues, while in parallel showed significantly improved PTC suppression activity in various in vitro, ex vivo and in vivo models for a variety of diseases underlined by PTC mutations. Although these derivatives hold great promise to serve as therapeutic candidates, they also demonstrate the necessity to further understand the molecular mechanisms by which AGs confer their biological activity in eukaryotic cells for further rational drug design. Recent achievements in structural research shed light on AGs' mechanism of action and opened up a new avenue in the development of new and improved therapeutic derivatives. The following manuscript highlights these accomplishments and summarizes their contributions to the state-of-art rational drug design.