RATIONAL DESIGN OF AMINOGLYCOSIDES AS A TOOL FOR THE TREATMENT OF HUMAN GENETIC DISEASES CAUSED BY NONSENCE MUTATIONS

Nonsense mutations result in the formation of truncated, nonfunctional proteins and account for about 12% of all mutations reported to date. In many cases, nonsense mutations might manifest as fatal diseases, including cystic fibrosis, Duchenne muscular dystrophy, Hurler syndrome and more. For many of these diseases there is presently no effective treatment other than symptomatic.

In the last several years, it has been demonstrated that some aminoglycoside antibiotics, such as gentamicin, G418 and paromomycin have an ability to induce translational readthrough of nonsense mutations via selective insertion of a near cognate tRNA at premature termination codons but not at normal stop codons, leading to the production of full length proteins. However, their use for the treatment of genetic diseases is quite restricted due to the relatively high toxicity values and low read-through activity prescribed upon their administration. To address these issues, during the last few years we have systematically developed new derivatives of aminoglycosides and demonstrated their improved read-through activity as well as decreased toxicity in comparison to the clinical aminoglycosides.

To further improve the performance of the developed leads, we used the most recent structural insights in the interaction of aminoglycosides with the eukaryotic ribosome, and describe here on the rational design of a new pseudo-disaccharide scaffold and new lead compounds derived from this scaffold structure. The new derivatives were synthesized and preliminary biological assays demonstrated significant improvement in their specificity and selectivity towards eukaryotic versus prokaryotic ribosome, and in their subsequent read-through activity in comparison to the related parent structures. Additional tests of the developed new lead compounds in various clinically relevant cellular and animal models of genetic diseases are currently underway.