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

被引：31
作者：
Bourguignon, Saulo C. [1 ]
Cavalcanti, Danielle F. B. [1 ]
de Souza, Alessandra M. T. [2 ,3 ]
Castro, Helena C. [1 ]
Rodrigues, Carlos R. [3 ]
Albuquerque, Magaly G. [4 ]
Santos, Dilvani O. [1 ]
da Silva, Gabriel Gomes [6 ]
da Silva, Fernando C. [2 ]
Ferreira, Vitor F. [2 ]
de Pinho, Rosa T. [5 ]
Alves, Carlos R. [6 ]
机构：
[1] Univ Fed Fluminense, Inst Biol, BR-24020150 Niteroi, RJ, Brazil
[2] Univ Fed Fluminense, Inst Quim, Dept Quim Organ, BR-24020150 Niteroi, RJ, Brazil
[3] Univ Fed Rio de Janeiro, Fac Farm, Lab Modelagem Mol & QSAR ModMolQSAR, BR-21944970 Rio De Janeiro, Brazil
[4] Univ Fed Rio de Janeiro, Inst Quim, Dept Quim Organ, Lab Modelagem Mol, BR-21941909 Rio De Janeiro, Brazil
[5] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Lab Imunol Clin, BR-21040900 Rio De Janeiro, Brazil
[6] Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Lab Biol Mol & Doencas Endem, BR-21040900 Rio De Janeiro, Brazil
来源：
EXPERIMENTAL PARASITOLOGY | 2011年 / 127卷 / 01期
关键词：
Chagas disease; Trypanosoma cruzi; Naphthoquinones; beta-Lapachone; Epoxy-alpha-lap; Proteinases; CYSTEINE PROTEINASES; OLIGOPEPTIDASE B; CELL INVASION; LAPACHONE; CHEMOTHERAPY; SPECIFICITY; INHIBITORS; SUBSTRATE; DISEASE; AGENTS;
D O I：
10.1016/j.exppara.2010.07.007
中图分类号：
R38 [医学寄生虫学]; Q [生物科学];
学科分类号：
07 ; 0710 ; 09 ; 100103 ;
摘要：
In this study we compared the effects of naphthoquinones (alpha-lapachone, beta-lapachone, nor-beta-lapachone and Epoxy-alpha-lap) on growth of Trypanosome 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 beta-lapachone and Epoxy-alpha-lap with a high trypanocidal activity in contrast to alpha-lapachone and nor-beta-lapachone whereas Epoxy-alpha-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. beta-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-alpha-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 beta-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-alpha-lap showed no important interactions. Overall, our results infer that beta-lapachone and Epoxy-alpha-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. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码：160 / 166
页数：7
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