Invited, NCK Award
Making sense from nonsense: Redesign of aminoglycosides for treatment of genetic diseases caused by nonsense mutations

Nonsense mutations that generate premature translation-termination codons (PTCs) are responsible for approximately one-third of human genetic diseases. Thousands of such mutations are known and several were shown to account cases of fatal diseases including cystic fibrosis, Duchenne muscular dystrophy, Hurler syndrome, several types of cancer and more. While major advancements have made in gene therapy, it is still far from achieving clinical success for the treatment of genetic diseases caused by PTCs. One alternative approach that has emerged recently is suppression of pathogenic PTCs through inducing translational read-through of the in-frame premature stop mutations. Aminoglycosides were the first drugs that gave promising results in this respect. However, high toxicity of these drugs and reduced suppression activity at sub-toxic doses has limited their clinical use in suppression therapy.

To address these issues, we have designed and synthesized a series of new derivatives of aminoglycosides, and their ability to read-through PTCs examined in both in-vitro and animal models of various diseases. By systematic tuning the structure-activity-toxicity relationship of the designed molecules, we developed five generations of lead structures; these leads demonstrated exceptional improvement in stop-codon read-through activity while maintained low toxicity. The research focuses on fundamental mechanistic aspects of aminoglycoside-induced read-through of PTCs and on the major chemical and biochemical mechanisms of aminoglycoside-induced toxicity to mammals. In this talk, the observed biochemical data will be analyzed in terms of structure-activity-toxicity relationships of designed structures; in terms of their eukaryotic versus prokaryotic selectivity and 3D crystal structures of designed molecules in complex with the ribosomal A-site RNA constructs. The most recent data on the developed lead compounds as potential anti-parasites, along with the new leads developed by using rational design approach, will also discussed.