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1.
Pathog Glob Health ; 108(1): 30-6, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24548158

RESUMO

The aim of the present study was to evaluate the effects of crude extracts from Handroanthus impetiginosa, Ageratum conyzoides, and Ruta graveolens on Leishmania amazonensis and Trypanosoma cruzi infection in vitro. The results showed that the extracts caused significant toxicity in promastigotes and trypomastigotes. A significant decrease in the rate of cell invasion by pretreated trypomastigotes and promastigotes was also observed. The extracts caused a significant reduction of the multiplication of intracellular amastigotes of both parasites. Therefore, these herbal extracts may be potential candidates for the development of drugs for the treatment of leishmaniasis and Chagas disease.


Assuntos
Antígenos de Protozoários/efeitos dos fármacos , Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fitoterapia/métodos , Preparações de Plantas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antígenos de Superfície/efeitos dos fármacos , Asteraceae/química , Bignoniaceae/química , Feminino , Imunofluorescência , Humanos , Masculino , Neuraminidase/efeitos dos fármacos , Proteínas de Protozoários/efeitos dos fármacos , Rutaceae/química , Tripanossomíase/tratamento farmacológico , Glicoproteínas Variantes de Superfície de Trypanosoma/efeitos dos fármacos
2.
Comb Chem High Throughput Screen ; 9(7): 491-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16925510

RESUMO

African trypanosomes are extracellular blood parasites that cause sleeping sickness in humans and Nagana in cattle. The therapeutics used to control and treat these diseases are very ineffective and thus, the development of new drugs is urgently needed. We have previously suggested to use trypanosome-specific RNA aptamers as tools for the development of novel trypanocidal compounds. Here, we report the selection of a 2'-NH(2)-modified RNA aptamer that binds to live trypanosomes with an affinity of 70 +/- 15 nM. The aptamer adopts a stable G-quartet structure and has a half-life in human serum of > 30 h. RNA binding is restricted to the flagellar attachment zone, located between the cell body and the flagellum of the parasite. We demonstrate that antigen-tagged preparations of the aptamer can bind to live trypanosomes and that they can be used to re-direct immunoglobulins to the parasite surface.


Assuntos
Aptâmeros de Nucleotídeos/farmacologia , RNA/farmacologia , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Glicoproteínas Variantes de Superfície de Trypanosoma/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos/uso terapêutico , Aptâmeros de Nucleotídeos/química , Sequência de Bases , Sítios de Ligação , Bovinos , Eletroforese em Gel de Poliacrilamida , Engenharia Genética/métodos , Humanos , Conformação de Ácido Nucleico , RNA/química , Tripanossomicidas/imunologia , Tripanossomíase Africana/genética , Tripanossomíase Africana/imunologia , Glicoproteínas Variantes de Superfície de Trypanosoma/genética , Glicoproteínas Variantes de Superfície de Trypanosoma/imunologia
3.
Eukaryot Cell ; 2(1): 84-94, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12582125

RESUMO

African trypanosomes cause sleeping sickness in humans and Nagana in cattle. The parasites multiply in the blood and escape the immune response of the infected host by antigenic variation. Antigenic variation is characterized by a periodic change of the parasite protein surface, which consists of a variant glycoprotein known as variant surface glycoprotein (VSG). Using a SELEX (systematic evolution of ligands by exponential enrichment) approach, we report the selection of small, serum-stable RNAs, so-called aptamers, that bind to VSGs with subnanomolar affinity. The RNAs are able to recognize different VSG variants and bind to the surface of live trypanosomes. Aptamers tethered to an antigenic side group are capable of directing antibodies to the surface of the parasite in vitro. In this manner, the RNAs might provide a new strategy for a therapeutic intervention to fight sleeping sickness.


Assuntos
Variação Antigênica/imunologia , RNA/imunologia , Trypanosoma brucei brucei/imunologia , Tripanossomíase Africana/imunologia , Glicoproteínas Variantes de Superfície de Trypanosoma/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Variação Antigênica/efeitos dos fármacos , Variação Antigênica/genética , Sequência de Bases/genética , Sítios de Ligação/genética , Desenho de Fármacos , Engenharia Genética/métodos , Ligantes , Conformação Molecular , Estrutura Molecular , RNA/genética , RNA/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/genética , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/genética , Glicoproteínas Variantes de Superfície de Trypanosoma/efeitos dos fármacos , Glicoproteínas Variantes de Superfície de Trypanosoma/genética
4.
Mol Biochem Parasitol ; 114(1): 111-7, 2001 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-11356520

RESUMO

Peptidomimetic inhibitors of mammalian zinc metalloproteases have been tested as potential agents for intervention in disease caused by kinetoplastid protozoa. Certain metalloprotease inhibitors were able to inhibit the release of variant surface glycoprotein from cultured transgenic procyclic Trypanosoma brucei, confirming our previous identification of a cell surface zinc metalloprotease activity in this stage of the trypanosome lifecycle [Bangs, JD et al. Expression of bloodstream variant surface glycoproteins in procyclic stage Trypanosoma brucei: role of GPI anchors in secretion, EMBO J. 1997;16:4285]. Selected peptidomimetics were also found to be toxic for cultured bloodstream trypanosomes with IC50 values in the low micromolar range. The paradigm for zinc metalloproteases in kinetoplastids are the GP63 surface enzymes of Leishmania. Peptidomimetics at low micromolar concentrations were able to inhibit in vitro cleavage of a synthetic peptide substrate by purified GP63 from L. major. Our results suggest that zinc metalloproteases perform essential functions in different stages of the trypanosome lifecycle and we hypothesize that these activities may be affected by the recently discovered trypanosomal homologues of GP63 [El-Sayed, NMA and Donelson, JE. African trypanosomes have differentially expressed genes encoding homologues of Leishmania GP63 surface protease, J. Biol. Chem. 1997;272:26742]. Development of higher affinity metalloprotease inhibitors may provide a novel avenue for treatment of parasitic diseases.


Assuntos
Antiprotozoários/farmacologia , Leishmania major/enzimologia , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Antiprotozoários/química , Cinética , Estrutura Molecular , Peptídeos/química , Inibidores de Proteases/química , Relação Estrutura-Atividade , Glicoproteínas Variantes de Superfície de Trypanosoma/efeitos dos fármacos
5.
Braz J Med Biol Res ; 29(3): 335-41, 1996 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8736126

RESUMO

Tc-85 is an 85-kDa surface glycoprotein specific for the trypomastigote stage of Trypanosoma cruzi which has been implicated in the invasion of host cells by the parasite. Tc-85 has a half-life of 3.5-4 h and is synthesized as a 95-kDa precursor. Processing of the 95-kDa precursor is inhibited by N-p-tosyl-L-lysine chloromethyl ketone, p-chloromercuriphenylsulfonic acid, iodoacetamide or N-ethylmaleimide, but not by aprotinin, antipain or phenylmethylsulfonil fluoride. Tc-85, but not the precursor, is rapidly shed into the medium, allowing a correlation between the decrease of Tc-85 in trypomastigotes and its increase in the culture medium. The shedding of Tc-85 was inhibited 50% by 1 microM tunicamycin, but not by 10 microM swainsonine or 10 microM 1-deoxynojirimycin under the experimental conditions employed. This suggests that N-linked oligosaccharides are important for the shedding phenomenon, although it appears that they do not have to be fully processed for shedding to occur.


Assuntos
Trypanosoma cruzi/metabolismo , Glicoproteínas Variantes de Superfície de Trypanosoma/efeitos dos fármacos , Animais , Eletroforese em Gel de Poliacrilamida , Glicoproteínas Variantes de Superfície de Trypanosoma/biossíntese , Glicoproteínas Variantes de Superfície de Trypanosoma/metabolismo
6.
Exp Parasitol ; 80(4): 633-44, 1995 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7758544

RESUMO

Transcripts which encode two metacyclic-form-specific variable surface glycoproteins (mVSGs) of Trypanosoma congolense IL3000 have been cloned into baculovirus expression vectors using a novel transfer vector, pAcL11. One of the recombinant baculoviruses (AcVSG1) expressed a mVSG as a glycoprotein with a signal peptide which was cleaved in this expression system, whereas the other one (AcVSG2) expressed an unprocessed protein. From 1 liter of culture containing 10(9) Spodoptera frugiperda cells infected with the recombinant baculoviruses, 10 and 30 mg of mVSG1 and mVSG2, respectively, were obtained. Monospecific polyclonal antibodies produced by immunization of mice with the recombinant proteins reacted specifically with the respective proteins and showed no cross-reactivities between mVSG1 and mVSG2 in immunoblot assays. The antibodies to each of the proteins stained only the surface of a proportion of intact fixed T. congolense IL3000 metacyclic forms. It was possible to determine from these studies that, on the average, the parasites expressing mVSG1 constitute approximately 45% of the metacyclic population of T. congolense IL3000 maintained in in vitro cultures, whereas those that express mVSG2 constitute approximately 20%.


Assuntos
Trypanosoma congolense/imunologia , Glicoproteínas Variantes de Superfície de Trypanosoma/biossíntese , Sequência de Aminoácidos , Animais , Anticorpos Antiprotozoários/biossíntese , Anticorpos Antiprotozoários/imunologia , Especificidade de Anticorpos , Baculoviridae/genética , Sequência de Bases , Linhagem Celular , Reações Cruzadas , Primers do DNA/química , Vetores Genéticos , Camundongos , Dados de Sequência Molecular , Mariposas , Plasmídeos , Reação em Cadeia da Polimerase , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/genética , Spodoptera/metabolismo , Tunicamicina/farmacologia , Glicoproteínas Variantes de Superfície de Trypanosoma/química , Glicoproteínas Variantes de Superfície de Trypanosoma/efeitos dos fármacos , Glicoproteínas Variantes de Superfície de Trypanosoma/genética
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