At the Society of Toxicology 58th Annual Meeting and ToxExpo from March 10th to 14th at the Baltimore Convention Center, Dr Jane Barber of ApconiX will be giving a talk as part of the Safety Assessment: Pharmaceutical—Drug Discovery I Platform on Monday March 11th 1:45pm – 2:00pm in Convention Center Room 321.
Target Safety Assessments: Evaluation of the Toxicological Risk of Targeting FRS (Phenylalanyl-tRNA Synthetase) in the Treatment of Malaria.
Authors: J. Barber1, C. Sadler1, D. Baud2, P. Willis2, and R. Roberts1,3.
1ApconiX, Alderley Edge, United Kingdom; 2Medicines for Malaria Venture, Geneva, Switzerland; and 3University of Birmingham, Birmingham, United Kingdom.
Phenylalanyl-tRNA synthetase (FRS) is a highly conserved enzyme that catalyzes the ligation of phenylalanine to its cognate transfer tRNA during protein synthesis. Due to its vital role as part of the translational machinery, FRS has been identified as a potential target to treat the malaria parasite. However, since target-related toxicity accounts for >50% of all drug project failures, it is vital to understand the potential unintended consequences of target modulation in non-plasmodium (mammalian) species to assist in the determination of the required plasmodium/human safety ratio. We conducted a comprehensive in silico target safety review to understand the role of FRS in normal physiology as a basis for evaluation of the potential toxicity of FRS inhibitors. Based on published literature, it is clear that eukaryotic cells harbour two different types of FRS: the heterotetrameric cytosolic alpha (FRSA) and beta forms, and the monomeric mitochondrial forms. Pathogenic variants in FRS2 (encoding the human mitochondrial FRS) have been associated with phenotypes ranging from spastic paraplegia to fatal infantile Alpers encephalopathy. FRSA knockout mice are homozygous lethal. Heterozygote phenotypes include abnormal bone morphology, decreased bone mineral density, decreased circulating chloride and sodium levels, impaired glucose tolerance and increased total body fat amount. Based on these observations, we predict that potential target organs of toxicity caused by inhibition of FRS could include bone, immune system, kidney, liver, muscle, and the nervous system. Specifically, there may be a risk of abnormal bone development, perturbed glucose metabolism, immunosuppression, nephrotoxicity, reduced liver function, myopathy and an increased risk of epilepsy. Based on this toxicological profile, inhibition of host FRS could be a serious limitation; therefore, the specificity and selectivity of compounds will be a key for their success. However, a single genomic copy of mitochondrial FRS is targeted to the parasite mitochondria and is exclusive to malaria parasites within the apicomplexan phyla, hence drug targeting of FRS presents a unique opportunity to potentially target malarial FRS specifically. Nonetheless, it would be sensible to conduct an early rodent investigative study looking at in life effects and potential target organs to help identify whether the risks our in silico analysis has identified actually occur in vivo with inhibitors of FRS.
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