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

• Grant number: 18/16672-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2019
• End date: February 28, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Cleslei Fernando Zanelli
• Grantee: Angélica Hollunder Klippel
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated research grant: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem), AP.TEM
• Associated scholarship(s): 19/24812-0 - Search for inhibitors of the enzyme deoxyhypusine synthase of eukaryotic organisms that cause neglected tropical diseases by high-throughput in vitro drug screening, BE.EP.DR

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.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SILVA, SUELEN FERNANDES; KLIPPEL, ANGELICA HOLLUNDER; RAMOS, PRISCILA ZONZINI; SANTIAGO, ANDREE DA SILVA; VALENTINI, SANDRO ROBERTO; BENGTSON, MARIO HENRIQUE; MASSIRER, KATLIN BRAUER; BILSLAND, ELIZABETH; COUNAGO, RAFAEL MIGUEZ; ZANELLI, CLESLEI FERNANDO. Structural features and development of an assay platform of the parasite target deoxyhypusine synthase of Brugia malayi and Leishmania major. PLoS Neglected Tropical Diseases, v. 14, n. 10, OCT 2020. (13/50724-5, 14/50897-0, 16/16970-7, 15/03553-6, 18/16672-1, 19/14275-8)

ALMEIDA, LUDIMILA DIAS; SILVA, ALI SALIM FARAJ; MOTA, DANIEL CALIXTO; VASCONCELOS, ADRIELLE AYUMI; CAMARGO, ANTONIO PEDRO; PIRES, GABRIEL SILVA; FURLAN, MONIQUE; FREIRE, HELENA MARTINS RIBEIRO DA CUNHA; KLIPPEL, ANGELICA HOLLUNDER; SILVA, SUELEN FERNANDES; et al. Yeast Double Transporter Gene Deletion Library for Identification of Xenobiotic Carriers in Low or High Throughput. MBIO, v. 12, n. 6, NOV-DEC 2021. (17/13015-7, 19/14146-3, 17/01986-8, 18/04240-0, 18/05328-8, 18/16672-1, 15/03553-6, 19/17876-2)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

KLIPPEL, Angélica Hollunder. Structural determination and search for inhibitors of the enzyme deoxy-hypusine synthase of eukaryotic organisms that cause neglected tropical diseases. 2023. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara Araraquara.