Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity

► Naphthoquinones derivatives decrease in vitro growth Trypanosoma cruzi. ► Cytotoxic activities of these compounds on mammalian VERO cells are dose-dependent. ► β-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi. ► Epoxy-α-lap is able to inhibit the serine-proteinase activi...

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Bibliographic Details
Published in:Experimental parasitology 2011, Vol.127 (1), p.160-166
Main Authors: Bourguignon, Saulo C., Cavalcanti, Danielle F.B., de Souza, Alessandra M.T., Castro, Helena C., Rodrigues, Carlos R., Albuquerque, Magaly G., Santos, Dilvani O., da Silva, Gabriel Gomes, da Silva, Fernando C., Ferreira, Vitor F., de Pinho, Rosa T., Alves, Carlos R.
Format: Article
Language:English
Subjects:
active sites
Animals
Anti-Infective Agents - pharmacology
Biological and medical sciences
Cercopithecus aethiops
Chagas disease
cruzipain
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors - pharmacology
drugs
epimastigotes
Epoxy-α-lap
Fundamental and applied biological sciences. Psychology
Human protozoal diseases
Infectious diseases
Leucine - analogs & derivatives
Leucine - pharmacology
Life cycle. Host-agent relationship. Pathogenesis
Medical sciences
molecular models
Naphthoquinones
Naphthoquinones - pharmacology
Parasitic diseases
parasitology
Peptide Hydrolases - drug effects
Peptide Hydrolases - metabolism
Protease Inhibitors - pharmacology
proteinase inhibitors
Proteinases
Protozoa
Protozoal diseases
Protozoan Proteins - antagonists & inhibitors
serine proteinases
toxicity
Trypanosoma cruzi
Trypanosoma cruzi - drug effects
Trypanosoma cruzi - enzymology
Trypanosoma cruzi - growth & development
Trypanosomiasis
Vero Cells
viability
β-Lapachone
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Summary:► Naphthoquinones derivatives decrease in vitro growth Trypanosoma cruzi. ► Cytotoxic activities of these compounds on mammalian VERO cells are dose-dependent. ► β-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi. ► Epoxy-α-lap is able to inhibit the serine-proteinase activity of T. cruzi. ► β-Lapachone and Epoxy-α-lap compounds may inhibit T. cruzi epimastigotes growth by affecting different proteinases. In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit T. cruzi epimastigotes growth by affecting T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds.
ISSN:0014-4894
1090-2449
DOI:10.1016/j.exppara.2010.07.007