Structural determination and search for inhibitors of the enzyme deoxy-hypusine synthase of eukaryotic organisms that cause neglected tropical diseases

Abstract

The eukaryotic translation factor 5A (eIF5A) is a highly conserved translation elongation factor in eukaryotes and it is essential for the viability of all organisms tested so far. eIF5A undergoes a specific post-translational modification, called hypusination, which is required for its function in the cell. Hypusination occurs in two steps, involving two different enzymes (deoxy-hypusine synthase (DHPS) and deoxy-hipusine hydroxylase) and considering the essentiality of hypusination and eIF5A, these enzymes are interesting targets for the development of inhibitors that may become new drugs. Thus, we proposed the search for structural differences between the DHPS enzyme (first step of hypusination) of pathogenic organisms and human enzyme that may be useful for the development of inhibitors more selective for the pathogens that cause neglected tropical diseases. DHPS is essential in all tested organisms and it is a potential target for therapeutic interventions, including those targeting human eukaryotic pathogens that cause neglected diseases. In addition, significant differences have already been described between the human enzyme and some parasites, which may contribute to discovery of specific drugs for these organisms. For this purpose, the deoxy-hypusine synthase sequences of the following pathogenic eukaryotic organisms were chosen for structural determination and search for inhibitors: Leishmania major, Plasmodium vivax, Paracoccidioides brasiliensis, Histoplasma capsulatum and Brugia malayi.