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Hypusinated EIF5A as a feasible drug target for Advanced Medicinal Therapies in the treatment of pathogenic parasites and therapy-resistant tumors

Abstract

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.

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Abbreviations

BSAO:

Bovine Serum Amine Oxidase

EIF5A:

Eukaryotic Initiation Factor 5A

CRISPR:

Clustered Regularly Interspaced Short Palindromic Repeats

DHS:

Deoxyhypusine synthase

DOHH:

Deoxyhypusine hydroxylase

HUVEC:

Human umbilical vein endothelial cells

5-LOX:

5-Lipoxygenase

Myc:

Transcription factor, name derives from an Avian virus Myelocytomatosis

PPI:

Protein–protein interaction

PTM:

Posttranslational modification

STAT:

Signal transducers and activators of transcription

TNF-α:

Tumor necrosis factor alpha

WNT:

Signaling pathway for immune cell maintenance and renewal

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Funding

Parts from this work were supported by ERANETPLUS 2019-446-3 to AK. The authors would like to thank the ‘International Polyamine Foundation ETS-ONLUS.

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Correspondence to Annette Kaiser.

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Both authors thoroughly edited the manuscript and approved the final draft. E.A. was responsible for the chapter of translational approaches with nanoparticles.

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Kaiser, A., Agostinelli, E. Hypusinated EIF5A as a feasible drug target for Advanced Medicinal Therapies in the treatment of pathogenic parasites and therapy-resistant tumors. Amino Acids 54, 501–511 (2022). https://doi.org/10.1007/s00726-021-03120-6

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Keywords

  • Hypusine
  • Cancer
  • Parasites
  • Advanced Medicinal Therapies