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Search for inhibitors of the peroxirredoxin system from pathogens and humans

Grant number: 17/19942-7
Support type:Regular Research Grants
Duration: April 01, 2018 - March 31, 2020
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Marcos Antonio de Oliveira
Grantee:Marcos Antonio de Oliveira
Home Institution: Instituto de Biociências (IB-CLP). Universidade Estadual Paulista (UNESP). Campus Experimental do Litoral Paulista. São Vicente , SP, Brazil
Assoc. researchers:Henrique Ferreira ; João Henrique Ghilardi Lago ; Luis Eduardo Soares Netto ; Marcelo Brocchi ; Marcos Hikari Toyama ; Rodrigo Luiz Oliveira Rodrigues Cunha

Abstract

Typical 2-Cys peroxiredoxins (2-Cys Prx) represent a group of antioxidant proteins able to decompose several types of hydroperoxides at rates of 105-8M-1s-1. These enzymes utilize a cysteine residue (peroxidatic cysteine - CP) which, after the peroxide decomposition, oxidizes (CP-SOH) forming a disulfide bond with a second cysteine which is reduced by the enzymes thioredoxin (Trx) and thioredoxin reductase (TrxR). The high reactivity of CP is achieved by interactions with a Thr (or Ser) residue and an Arg, which are so called the catalytic triad. 2-Cys Prx are very abundant among the organisms and their expressions are enhanced in genetic diseases, as cancer, and infectious diseases caused by bacteria and fungi. Inhibition these enzymes significantly reduces the growth of tumor cells or the pathogens establishment. However, most of the studies did not verify for possible effects of these inhibitors on reducing system of the typical 2-Cys Prx. Additionally, it was not investigated if molecules initially used for the inhibition mammalian peroxidases can also inhibit enzymes from other organisms, such as pathogens. In fact the mammalian 2-Cys Prx reducing system is very distinct from other organisms like pathogenic bacteria and fungi. Our research group elucidated the first 2-Cys Prx structure of eukaryotes with the presence of a ligand in the active site pocket and recently we have demonstrated that the natural substitution of the catalytic triad Thr by Ser results in dramatic structural and functional changes of the typical 2-Cys Prx. Preliminary results from our research group are very promising since they demonstrate that Adenantin (Adn), a molecule identified as an inhibitor of human 2-Cys Prx, is more potent in the inhibition of the 2-Cys Prx containing a Ser in the active site. The sequence analysis of the 2-Cys Prx revealed that the Thr ’ Ser substitution is almost inexistent in multicellular organisms, but is often found in pathogenic bacteria. Cytotoxicity assays indicated that Adn has low toxicity to Escherichia coli, which contain a Thr in the catalytic triad, but is very toxic to bacteria that possess Ser in the catalytic triad, as the pathogens Staphylococcus aureus and Staphylococcus epidermidis. However, additional studies are needed to understand the mechanism of action and its potential for use as a bactericidal agent. Adn is a molecule belonging to the group of ent-cauranic diterpenoids, which are widely distributed in plants. In Brazil derived from ent-cauran skeleton were isolated from plants of different biomes, but their application in the inhibition of 2-Cys Prx has never been tested. In addition, it has also been demonstrated that organic compounds derived from selenium (Se) and tellurium (Te) are able to inhibit enzymes which activity is resident in thiols as cysteine proteases, protein tyrosine kinases and TrxR, however, studies aiming the evaluation of these kind of inhibitors over the 2-Cys Prx and their reducing systems from different organisms are inexistent in the literature. The goals of this project resides in the search of bioactive molecules able to inhibit differentially the typical 2-Cys Prx containing Thr or Ser as part of the catalytic triad and/or their reductant systems, in bacteria, fungi and human. The molecules that will be tested are ent-cauranic diterpenoids isolated from blats of the Brazilian biota (natural or chemically modified) as well synthetic molecules based on Se and Te. To reach the objectives this project counts with the collaboration of chemists specialized in isolation, modification and synthesis of molecules and microbiologists. Finally, for molecules available in adequate quantities we intend to perform co-crystallization assays (enzyme + inhibitor) in order to determine the crystallographic structure of the complexes. (AU)

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)
COSTA, CAROLINE R. C.; BELCHOR, MARIANA NOVO; RODRIGUES, CAROLINE F. B.; TOYAMA, DANIELA DE OLIVEIRA; DE OLIVEIRA, MARCOS A.; NOVAES, DANIELLE P.; TOYAMA, MARCOS HIKARI. Edema Induced by a Crotalus durissus terrificus Venom Serine Protease (Cdtsp 2) Involves the PAR Pathway and PKC and PLC Activation. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, n. 8 AUG 2018. Web of Science Citations: 1.

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