Nonsense mutations can lead to the formation of truncated, defective proteins that cause rare genetic diseases and cancer. Aminoglycosides, traditionally used as Gram-negative antibacterial agents, can be used to induce readthrough of premature termination codon (PTC) to treat genetic disorders caused by nonsense mutations. Aminoglycosides bind to ribosomes, change their conformation, and allow for the incorporation of an amino acid, suppressing premature translation termination. This leads to a rescue of protein function.
Aminoglycosides as PTC readthrough reagents
Aminoglycosides are typically produced as complex mixtures by fermentation of Gram-positive bacteria, and the challenges associated with isolating pure components from these mixtures have complicated their study. Access to pure synthetic analogues is vital to the development of novel aminoglycosides with favourable therapeutic profiles. Though this class of compounds are attractive targets, the clinical toxicity profile of aminoglycosides present a challenge to their development as PTC readthrough agents. Aminoglycosides are nephrotoxic and ototoxic, and their mechanism of toxicity is thought to be driven by accumulation and retention in the cochlear cells and proximal tubule cells.
One strategy to reduce toxicity is to reduce the cationic charge of the molecule. Previous studies have demonstrated that reducing the basic sites from the sisomicin skeleton at physiological pH reduced ototoxicity without compromising readthrough activity.
Expertise in complex carbohydrate synthesis
In 2017, GlycoSyn was approached by a client to chemically synthesize library of difficult to access PTC readthrough agents with modified amino groups in an attempt to reduce ototoxicity. After identifying the paramamine core as a scaffold, we applied our structural modification onto the core of NB124 (ELX-02), an aminoglycoside derivative in phase II clinical trials for treatment of cystic fibrosis and nephropathic cystinosis. Our synthetic efforts have illuminated the role of the amino and hydroxyl groups at the 6’- and 2’-position of Ring I, with the goal of reducing the overall cationic charge of the parent molecules in an attempt to widen the therapeutic window of these compounds. Our efforts resulted in the identification of a lead compound as a promising analogue. Further evaluation of the in vivo properties and readthrough activity assessment of the toxicity profile remains ongoing.
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Publication Date: August 9, 2021