Identification of a peptide derived from a Bothrops moojeni metalloprotease with in vitro inhibitory action on the Plasmodium falciparum purine nucleoside phosphorylase enzyme (PfPNP).

Autor: Martins GG; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil; São Lucas University Center, UniSL, Porto Velho, Rondônia, Brazil. Electronic address: graci_anny@hotmail.com., de Jesus Holanda R; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil., Alfonso J; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil., Gómez Garay AF; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil., Dos Santos APA; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil; Malaria and Leishmaniasis Bioassay Platform, PBML, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil., de Lima AM; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil., Francisco AF; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil., Garcia Teles CB; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil; São Lucas University Center, UniSL, Porto Velho, Rondônia, Brazil; Malaria and Leishmaniasis Bioassay Platform, PBML, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil., Zanchi FB; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil., Soares AM; Center for the Study of Biomolecules Applied to Health, CEBio, Oswaldo Cruz Foundation Rondônia, FIOCRUZ, Porto Velho, Rondônia, Brazil; Graduate Program in Experimental Biology, PGBIOEXP, Federal University of Rondônia, UNIR, Porto Velho, Rondônia, Brazil; National Institute of Science and Technology in Epidemiology of the Western Amazonia, INCT-EpiAmO, Porto Velho, Rondônia, Brazil; São Lucas University Center, UniSL, Porto Velho, Rondônia, Brazil.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2019 Jul; Vol. 162, pp. 97-106. Date of Electronic Publication: 2019 Apr 09.
DOI: 10.1016/j.biochi.2019.04.009
Abstrakt: There is a growing need for research on new antimalarial agents against Plasmodium falciparum infection, especially in regards to planning molecular architecture for specific molecular targets of the parasite. Thus, a metalloprotease from Bothrops moojeni, known as BmooMPα-I, was explored in this study, through in silico assays, aiming at the development of a peptide generated from this molecule with potential inhibitory action on PfPNP, an enzyme necessary for the survival of the parasite. In order to isolate BmooMPα-I, cation exchange and reverse phase chromatographies were performed, followed by in vitro assays of antiparasitic activity against the W2 strain of P. falciparum. The interactions between BmooMPα-I and PfPNP were evaluated via docking, and the resulting peptide, described as Pep1 BM, was selected according to the BmooMPα-I region demonstrating the best interaction score with the target of interest. The values for the specific activities of the PfPNP reaction were measured using the inorganic phosphate substrate and MESG. The fraction corresponding to BmooMPα-I was identified as fraction 4 in the cation exchange chromatography step, due to proteolytic activity on casein and the presence of a major band at ≅ 23 kDa. BmooMPα-I was able to inhibit in vitro growth of W2 P. falciparum, with an IC 50 value of 16.14 μg/mL. Virtual screening with Pep1 BM demonstrated two PfPNP target binding regions, with ΔG values at the interaction interface of -10.75 kcal/mol and -11.74 kcal/mol. A significant reduction in the enzymatic activity of PfPNP was observed in the presence of Pep 1 BM when compared to the assay in the absence of this possible inhibitor. BmooMPα-I showed activity in vitro against W2 P. falciparum. By means of in silico techniques, the Pep 1 BM was identified as having potential binding affinity to the catalytic site of PfPNP and of inhibiting its catalytic activity in vitro.
(Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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