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Cancer drug resistance, in particular in advanced stages such as metastasis and invasion is an emerging problem. Moreover, drug resistance of parasites causing poverty-related diseases is an enormous, global challenge for drug development in the future. To circumvent this problem of increasing resistance, the development of either novel small compounds or Advanced Medicinal Therapies have to be fostered. Polyamines have many fundamental cellular functions like DNA stabilization, protein translation, ion channel regulation, autophagy, apoptosis and mostly important, cell proliferation. Consequently, many antiproliferative drugs can be commonly administered either in cancer therapy or for the treatment of pathogenic parasites. Most important for cell proliferation is the triamine spermidine, since it is an important substrate in the biosynthesis of the posttranslational modification hypusine in eukaryotic initiation factor 5A (EIF5A). To date, no small compound has been identified that directly inhibits the precursor protein EIF5A. Moreover, only a few small molecule inhibitors of the two biosynthetic enzymes, i.e. deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) have been functionally characterized. However, it is evident that only some of the compounds have been applied in translational approaches, i.e. in murine models to analyze the function of this modified protein in cell proliferation. In recent years, the pharmaceutical industry shifted from small molecules beyond traditional pharmacology to new tools and methods to treat disorders involving signaling deregulation. In this review, we evaluate translational approaches on inhibition of EIF5A hypusination in pathogenic parasites and therapy-resistant tumors and discuss its feasibility for an application in Advanced Medicinal Therapies. © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.

Citation

Annette Kaiser, Enzo Agostinelli. Hypusinated EIF5A as a feasible drug target for Advanced Medicinal Therapies in the treatment of pathogenic parasites and therapy-resistant tumors. Amino acids. 2022 Apr;54(4):501-511

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PMID: 35000000

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