Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
1.
Malar J ; 21(1): 6, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983540

RESUMO

BACKGROUND: The GMZ2.6c malaria vaccine candidate is a multi-stage Plasmodium falciparum chimeric protein which contains a fragment of the sexual-stage Pfs48/45-6C protein genetically fused to GMZ2, a fusion protein of GLURP and MSP-3, that has been shown to be well tolerated, safe and immunogenic in clinical trials performed in a malaria-endemic area of Africa. However, there is no data available on the antigenicity or immunogenicity of GMZ2.6c in humans. Considering that circulating parasites can be genetically distinct in different malaria-endemic areas and that host genetic factors can influence the immune response to vaccine antigens, it is important to verify the antigenicity, immunogenicity and the possibility of associated protection in individuals living in malaria-endemic areas with different epidemiological scenarios. Herein, the profile of antibody response against GMZ2.6c and its components (MSP-3, GLURP and Pfs48/45) in residents of the Brazilian Amazon naturally exposed to malaria, in areas with different levels of transmission, was evaluated. METHODS: This study was performed using serum samples from 352 individuals from Cruzeiro do Sul and Mâncio Lima, in the state of Acre, and Guajará, in the state of Amazonas. Specific IgG, IgM, IgA and IgE antibodies and IgG subclasses were detected by Enzyme-Linked Immunosorbent Assay. RESULTS: The results showed that GMZ2.6c protein was widely recognized by naturally acquired antibodies from individuals of the Brazilian endemic areas with different levels of transmission. The higher prevalence of individuals with antibodies against GMZ2.6c when compared to its individual components may suggest an additive effect of GLURP, MSP-3, and Pfs48/45 when inserted in a same construct. Furthermore, naturally malaria-exposed individuals predominantly had IgG1 and IgG3 cytophilic anti-GMZ2.6c antibodies, an important fact considering that the acquisition of anti-malaria protective immunity results from a delicate balance between cytophilic/non-cytophilic antibodies. Interestingly, anti-GMZ2.6c antibodies seem to increase with exposure to malaria infection and may contribute to parasite immunity. CONCLUSIONS: The data showed that GMZ2.6c protein is widely recognized by naturally acquired antibodies from individuals living in malaria-endemic areas in Brazil and that these may contribute to parasite immunity. These data highlight the importance of GMZ2.6c as a candidate for an anti-malarial vaccine.


Assuntos
Formação de Anticorpos , Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Glicoproteínas de Membrana/imunologia , Fragmentos de Peptídeos/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Mem Inst Oswaldo Cruz ; 114: e190054, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31411308

RESUMO

BACKGROUND: The central repetitive region (CRR) of the Plasmodium vivax circumsporozoite surface protein (CSP) is composed of a repetitive sequence that is characterised by three variants: VK210, VK247 and P. vivax-like. The most important challenge in the treatment of P. vivax infection is the possibility of differential response based on the parasite genotype. OBJECTIVES: To characterise the CSP variants in P. vivax isolates from individuals residing in a malaria-endemic region in Brazil and to profile these variants based on sensitivity to chloroquine and mefloquine. METHODS: The CSP variants were determined by sequencing and the sensitivity of the P. vivax isolates to chloroquine and mefloquine was determined by Deli-test. FINDINGS: Although five different allele sizes were amplified, the sequencing results showed that all of the isolates belonged to the VK210 variant. However, we observed substantial genetic diversity in the CRR, resulting in the identification of 10 different VK210 subtypes. The frequency of isolates that were resistant to chloroquine and mefloquine was 11.8 and 23.8%, respectively. However, we did not observe any difference in the frequency of the resistant isolates belonging to the VK210 subtypes. MAIN CONCLUSION: The VK210 variant is the most frequently observed in the studied region and there is significant genetic variability in the CRR of the P. vivax CSP. Moreover, the antimalarial drug sensitivity profiles of the isolates does not seem to be related to the VK210 subtypes.


Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Malária Vivax/parasitologia , Mefloquina/farmacologia , Plasmodium vivax/efeitos dos fármacos , Proteínas de Protozoários/genética , Genótipo , Humanos , Testes de Sensibilidade Parasitária , Plasmodium vivax/genética , Plasmodium vivax/isolamento & purificação , Reação em Cadeia da Polimerase
4.
Malar J ; 17(1): 338, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30249260

RESUMO

BACKGROUND: Zoonotic infections with epidemic potential, as non-human primate malaria and yellow fever (YF), can overlap geographically. Optimizing a small blood sample for diagnosis and surveillance is of great importance. Blood are routinely collected for YF diagnosis and blood clots usually discarded after serum obtention. Aiming to take sample advantage, the sensitivity of a PCR using extracted DNA from long-term frozen clots from human and non-human primates for detection of Plasmodium spp. in low parasitaemia conditions was assayed. RESULTS: Malaria diagnosis with DNA extracted from blood clots generated results in agreement with samples obtained with whole blood, including mixed Plasmodium vivax/simium and Plasmodium malariae/brasilianum infections. CONCLUSION: Blood clots from human and non-human primates may be an important and low cost source of DNA for malaria surveillance in the Atlantic Forest.


Assuntos
Alouatta , Callithrix , Coinfecção/veterinária , Malária/veterinária , Doenças dos Macacos/diagnóstico , Plasmodium/isolamento & purificação , Animais , Brasil , Coinfecção/diagnóstico , Coinfecção/parasitologia , Humanos , Malária/diagnóstico , Malária/parasitologia , Malária Vivax/diagnóstico , Malária Vivax/parasitologia , Malária Vivax/veterinária , Doenças dos Macacos/parasitologia , Plasmodium/classificação , Plasmodium malariae/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Trombose/parasitologia
5.
Mem Inst Oswaldo Cruz ; 113(8): e170452, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29924131

RESUMO

BACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years. METHODS Thirty compounds were synthesised employing the Biginelli multicomponent reaction and subsequent one-pot substitution/cyclisation protocol; the compounds were then evaluated in vitro against chloroquine-resistant Plasmodium falciparum parasites (W2 strain). Drug cytotoxicity in baseline kidney African Green Monkey cells (BGM) was also evaluated. The most active in vitro compounds were evaluated against P. berghei parasites in mice. Additionally, we performed an in silico target fishing approach with the most active compounds, aiming to shed some light into the mechanism at a molecular level. RESULTS The synthetic route chosen was effective, leading to products with high purity and yields ranging from 10-84%. Three out of the 30 compounds tested were identified as active against the parasite and presented low toxicity. The in silico study suggested that among all the molecular targets identified by our target fishing approach, Protein Kinase 3 (PK5) and Glycogen Synthase Kinase 3ß (GSK-3ß) are the most likely molecular targets for the synthesised compounds. CONCLUSIONS We were able to easily obtain a collection of heterocyclic compounds with in vitro anti-P. falciparum activity that can be used as scaffolds for the design and development of new antiplasmodial drugs.


Assuntos
Antimaláricos/síntese química , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirimidinonas/síntese química , Pirróis/síntese química , Animais , Antimaláricos/farmacologia , Desenho de Fármacos , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Testes de Sensibilidade Parasitária , Pirimidinonas/farmacologia , Pirróis/farmacologia , Relação Estrutura-Atividade
6.
Malar J ; 14: 166, 2015 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-25927834

RESUMO

BACKGROUND: The neotropical, non-human primates (NHP) of the genus Saimiri and Aotus are recommended by the World Health Organization as experimental models for the study of human malaria because these animals can be infected with the same Plasmodium that cause malaria in humans. However, one limitation is the lack of immunological tools to assess the immune response in these models. The present study focuses on the development and comparative use of molecular and immunological methods to evaluate the cellular immune response in Saimiri sciureus. METHODS: Blood samples were obtained from nineteen uninfected Saimiri. Peripheral blood mononuclear cells (PBMC) from these animals and splenocytes from one splenectomized animal were cultured for 6, 12, 18, 24, 48, 72 and 96 hrs in the presence of phorbol-12-myristate-13-acetate and ionomycin. The cytokine levels in the supernatant were detected using human and NHP cytometric bead array Th1/Th2 cytokine kits, the Bio-Plex Pro Human Cytokine Th1/Th2 Assay, enzyme-linked immunosorbent assay, enzyme-linked immunospot assays and intracellular cytokine secretion assays. Cytokine gene expression was examined through TaqMan® Gene Expression Real-Time PCR using predesigned human gene-specific primers and probes or primers and probes designed based on published S. sciureus cytokine sequences. RESULTS: The use of five assays based on monoclonal antibodies specific for human cytokines facilitated the detection of IL-2, IL-4 and/or IFN-γ. TaqMan array plates facilitated the detection of 12 of the 28 cytokines assayed. However, only seven cytokines (IL-1A, IL-2, IL-10, IL-12B, IL-17, IFN-ß, and TNF) presented relative expression levels of at least 70% of the gene expression observed in human PBMC. The use of primers and probes specific for S. sciureus cytokines facilitated the detection of transcripts that showed relative expression below the threshold of 70%. The most efficient evaluation of cytokine gene expression, in PBMC and splenocytes, was observed after 6-12 hrs of culture, except for LTA in PBMC, whose expression was best analysed after 24 hrs of culture. CONCLUSIONS: Real-time PCR facilitates the analysis of a large number of cytokines altered during malaria infection, and this technique is considered the best tool for the evaluation of the cellular immune response in S. sciureus.


Assuntos
Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , ELISPOT/métodos , Imunidade Celular , Malária/imunologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Saimiri/imunologia , Animais , Modelos Animais de Doenças , Leucócitos Mononucleares
7.
Malar J ; 12: 281, 2013 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-23937727

RESUMO

BACKGROUND: The emergence and spread of Plasmodium falciparum and Plasmodium vivax resistance to available anti-malarial drugs represents a major drawback in the control of malaria and its associated morbidity and mortality. The aim of this study was to evaluate the chemoresistance profile of P. falciparum and P. vivax to commonly used anti-plasmodial drugs in a malaria-endemic area in the Brazilian Amazon. METHODS: The study was carried out in Manaus (Amazonas state), in the Brazilian Amazon. A total of 88 P. falciparum and 178 P. vivax isolates was collected from 2004 to 2007. The sensitivity of P. falciparum isolates was determined to chloroquine, quinine, mefloquine and artesunate and the sensitivity of P. vivax isolates was determined to chloroquine and mefloquine, by using the colorimetric DELI test. RESULTS: As expected, a high prevalence of P. falciparum isolates resistant to chloroquine (78.1%) was observed. The prevalence of isolates with profile of resistance or decreased sensitivity for quinine, mefloquine and artesunate was 12.7, 21.2 and 11.7%, respectively. In the case of P. vivax, the prevalence of isolates with profile of resistance for chloroquine and mefloquine was 9.8 and 28%, respectively. No differences in the frequencies of isolates with profile of resistance or geometric mean IC50s were seen when comparing the data obtained in 2004, 2005, 2006 and 2007, for all tested anti-malarials. CONCLUSIONS: The great majority of P. falciparum isolates in the Brazilian malaria-endemic area remain resistant to chloroquine, and the decreased sensitivity to quinine, mefloquine and artesunate observed in 10-20% of the isolates must be taken with concern, especially for artesunate. Plasmodium vivax isolates also showed a significant proportion of isolates with decreased sensitivity to chloroquine (first-line drug) and mainly to mefloquine. The data presented here also confirm the usefulness of the DELI test to generate results able to impact on public health policies.


Assuntos
Antimaláricos/farmacologia , Colorimetria , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/isolamento & purificação , Adulto , Brasil , Resistência a Medicamentos , Feminino , Humanos , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Testes de Sensibilidade Parasitária , Prevalência , Adulto Jovem
8.
PLoS Negl Trop Dis ; 13(12): e0007906, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31815937

RESUMO

BACKGROUND: Although malaria cases have substantially decreased in Southeast Brazil, a significant increase in the number of Plasmodium vivax-like autochthonous human cases has been reported in remote areas of the Atlantic Forest in the past few decades in Rio de Janeiro (RJ) state, including an outbreak during 2015-2016. The singular clinical and epidemiological aspects in several human cases, and collectively with molecular and genetic data, revealed that they were due to the non-human primate (NHP) parasite Plasmodium simium; however, the understanding of the autochthonous malarial epidemiology in Southeast Brazil can only be acquired by assessing the circulation of NHP Plasmodium in the foci and determining its hosts. METHODOLOGY: A large sampling effort was carried out in the Atlantic forest of RJ and its bordering states (Minas Gerais, São Paulo, Espírito Santo) for collecting and examining free-living NHPs. Blood and/or viscera were analyzed for Plasmodium infections via molecular and microscopic techniques. PRINCIPAL FINDINGS: In total, 146 NHPs of six species, from 30 counties in four states, were tested, of which majority were collected from RJ. Howler monkeys (Alouatta clamitans) were the only species found infected. In RJ, 26% of these monkeys tested positive, of which 17% were found to be infected with P. simium. Importantly, specific single nucleotide polymorphisms-the only available genetic markers that differentiate P. simium from P. vivax-were detected in all P. simium infected A. clamitans despite their geographical origin of malarial foci. Interestingly, 71% of P. simium infected NHPs were from the coastal slope of a mountain chain (Serra do Mar), where majority of the human cases were found. Plasmodium brasilianum/malariae was initially detected in 14% and 25% free-living howler monkeys in RJ and in the Espírito Santo (ES) state, respectively. Moreover, the malarial pigment was detected in the spleen fragments of 50% of a subsample comprising dead howler monkeys in both RJ and ES. All NHPs were negative for Plasmodium falciparum. CONCLUSIONS/SIGNIFICANCE: Our data indicate that howler monkeys act as the main reservoir for the Atlantic forest human malarial parasites in RJ and other sites in Southeast Brazil and reinforce its zoonotic characteristics.


Assuntos
Alouatta/parasitologia , Reservatórios de Doenças/parasitologia , Malária/veterinária , Doenças dos Macacos/epidemiologia , Plasmodium/classificação , Plasmodium/isolamento & purificação , Zoonoses/epidemiologia , Animais , Sangue/parasitologia , Brasil , Florestas , Humanos , Malária/epidemiologia , Malária/parasitologia , Doenças dos Macacos/parasitologia , Zoonoses/parasitologia
9.
Front Immunol ; 8: 1814, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29312325

RESUMO

Non-human primates (NHP) are suitable models for studying different aspects of the human system, including pathogenesis and protective immunity to many diseases. However, the lack of specific immunological reagents for neo-tropical monkeys, such as Saimiri sciureus, is still a major factor limiting studies in these models. An alternative strategy to circumvent this obstacle has been the selection of immunological reagents directed to humans, which present cross-reactivity with NHP molecules. In this context and considering the key role of inhibitory immunoreceptors-such as the signal regulatory protein α (SIRPα)-in the regulation of immune responses, in the present study, we attempted to evaluate the ability of anti-human SIRPα monoclonal antibodies to recognize SIRPα in antigen-presenting S. sciureus peripheral blood mononuclear cells (PBMC). As shown by flow cytometry analysis, the profile of anti-SIRPα staining as well as the levels of SIRPα-positive cells in PBMC from S. sciureus were similar to those observed in human PBMC. Furthermore, using anti-SIRPα monoclonal antibody, it was possible to detect a decrease of the SIRPα levels on surface of S. sciureus cells after in vitro stimulation with lipopolysaccharides. Finally, using computed-based analysis, we observed a high degree of conservation of SIRPα across six species of primates and the presence of shared epitopes in the extracellular domain between humans and Saimiri genus that could be targeted by antibodies. In conclusion, we have identified a commercially available anti-human monoclonal antibody that is able to detect SIRPα of S. sciureus monkeys and that, therefore, can facilitate the study of the immunomodulatory role of SIRPα when S. sciureus is used as a model.

10.
Artigo em Inglês | MEDLINE | ID: mdl-28983468

RESUMO

A major constraint in the study of Plasmodium falciparum malaria, including vaccine development, lies on the parasite's strict human host specificity and therefore the shortage of animal experimental models able to harbor human plasmodia. The best experimental models are neo-tropical primates of the genus Saimiri and Aotus, but they require splenectomy to reduce innate defenses for achieving high and consistent parasitemias, an important limitation. Clodronate-liposomes (CL) have been successfully used to deplete monocytes/macrophages in several experimental models. We investigated whether a reduction in the numbers of phagocytic cells by CL would improve the development of P. falciparum parasitemia in non-splenectomized Saimiri sciureus monkeys. Depletion of S. sciureus splenocytes after in vitro incubation with CL was quantified using anti-CD14 antibodies and flow cytometry. Non-infected and P. falciparum-infected S. sciureus were injected intravenously twice a week with either CL at either 0.5 or 1 mL (5 mg/mL) or phosphate buffered saline (PBS). Animals were monitored during infection and treated with mefloquine. After treatment and euthanasia, spleen and liver were collected for histological analysis. In vitro CL depleted S. sciureus splenic monocyte/macrophage population in a dose- and time-dependent manner. In vivo, half of P. falciparum-infected S. sciureus treated with CL 0.5 mL, and two-thirds of those treated with CL 1 mL developed high parasitemias requiring mefloquine treatment, whereas all control animals were able to self-control parasitemia without the need for antimalarial treatment. CL-treated infected S. sciureus showed a marked decrease in the degree of splenomegaly despite higher parasitemias, compared to PBS-treated animals. Histological evidence of partial monocyte/macrophage depletion, decreased hemozoin phagocytosis and decreased iron recycling was observed in both the spleen and liver of CL-treated infected S. sciureus. CL is capable of promoting higher parasitemia in P. falciparum-infected S. sciureus, associated with evidence of partial macrophage depletion in the spleen and liver. Macrophage depletion by CL is therefore a practical and viable alternative to surgical splenectomy in this experimental model.


Assuntos
Ácido Clodrônico/farmacologia , Macrófagos/efeitos dos fármacos , Malária Falciparum/parasitologia , Monócitos/efeitos dos fármacos , Parasitemia/induzido quimicamente , Plasmodium falciparum/crescimento & desenvolvimento , Animais , Ácido Clodrônico/administração & dosagem , Modelos Animais de Doenças , Feminino , Haplorrinos , Humanos , Lipossomos , Fígado/citologia , Masculino , Fagocitose/efeitos dos fármacos , Saimiri , Baço/citologia , Fatores de Tempo
11.
Artigo em Português | Arca: Repositório institucional da Fiocruz | ID: arc-49059

RESUMO

A malária continua sendo um dos principais problemas globais de saúde pública, sendo responsável pela morte de 409.000 pessoas anualmente, principalmente devido à infecção por Plasmodium falciparum. Assim, o desenvolvimento de uma vacina tem sido uma das prioridades de pesquisa para o enfrentamento desse problema. Não existe vacina licenciada contra a malária e, embora mais de 30 antígenos tenham sido identificados como candidatos vacinais, nenhum deles gerou uma perspectiva sólida de que uma vacina possa estar disponível nos próximos anos. Torna-se fundamental a pesquisa de candidatos vacinais mais imunogênicos, eficazes e seguros. Os primatas neotropicais dos gêneros Saimiri e Aotus são os modelos recomendados para estudos experimentais em malária, visto que podem ser infectados por plasmódios humanos. O Laboratório de Pesquisa em Malária (LabMal) da Fundação Oswaldo Cruz estuda os mecanismos de defesa e doença na malária e utiliza os modelos Saimiri e Aotus para a avaliação pré-clínica de antígenos candidatos à vacina e estudos de mecanismos de aquisição de imunidade e fisiopatogenia da malária. Para a realização dos estudos, o LabMal estabeleceu uma parceria com o Centro Nacional de Primatas (CENP) do Instituto Evandro Chagas, que resultou na ampliação das colônias de Saimiri sciureus, colocando o CENP entre as raras instituições no mundo que dispõem desse recurso para pesquisa. O presente trabalho é um retrospecto dos resultados obtidos durante 25 anos de parceria entre o LabMal e o CENP na utilização de primatas Saimiri e Aotus como modelos de estudo para pesquisa e desenvolvimento de uma vacina antimalárica.

12.
Mem. Inst. Oswaldo Cruz ; 114: e190054, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1012675

RESUMO

BACKGROUND The central repetitive region (CRR) of the Plasmodium vivax circumsporozoite surface protein (CSP) is composed of a repetitive sequence that is characterised by three variants: VK210, VK247 and P. vivax-like. The most important challenge in the treatment of P. vivax infection is the possibility of differential response based on the parasite genotype. OBJECTIVES To characterise the CSP variants in P. vivax isolates from individuals residing in a malaria-endemic region in Brazil and to profile these variants based on sensitivity to chloroquine and mefloquine. METHODS The CSP variants were determined by sequencing and the sensitivity of the P. vivax isolates to chloroquine and mefloquine was determined by Deli-test. FINDINGS Although five different allele sizes were amplified, the sequencing results showed that all of the isolates belonged to the VK210 variant. However, we observed substantial genetic diversity in the CRR, resulting in the identification of 10 different VK210 subtypes. The frequency of isolates that were resistant to chloroquine and mefloquine was 11.8 and 23.8%, respectively. However, we did not observe any difference in the frequency of the resistant isolates belonging to the VK210 subtypes. MAIN CONCLUSION The VK210 variant is the most frequently observed in the studied region and there is significant genetic variability in the CRR of the P. vivax CSP. Moreover, the antimalarial drug sensitivity profiles of the isolates does not seem to be related to the VK210 subtypes.


Assuntos
Plasmodium vivax/efeitos dos fármacos , Mefloquina/uso terapêutico , Cloroquina/uso terapêutico , Resistência a Múltiplos Medicamentos/imunologia , Brasil
13.
Mem. Inst. Oswaldo Cruz ; 113(8): e170452, 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-955116

RESUMO

BACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years. METHODS Thirty compounds were synthesised employing the Biginelli multicomponent reaction and subsequent one-pot substitution/cyclisation protocol; the compounds were then evaluated in vitro against chloroquine-resistant Plasmodium falciparum parasites (W2 strain). Drug cytotoxicity in baseline kidney African Green Monkey cells (BGM) was also evaluated. The most active in vitro compounds were evaluated against P. berghei parasites in mice. Additionally, we performed an in silico target fishing approach with the most active compounds, aiming to shed some light into the mechanism at a molecular level. RESULTS The synthetic route chosen was effective, leading to products with high purity and yields ranging from 10-84%. Three out of the 30 compounds tested were identified as active against the parasite and presented low toxicity. The in silico study suggested that among all the molecular targets identified by our target fishing approach, Protein Kinase 3 (PK5) and Glycogen Synthase Kinase 3β (GSK-3β) are the most likely molecular targets for the synthesised compounds. CONCLUSIONS We were able to easily obtain a collection of heterocyclic compounds with in vitro anti-P. falciparum activity that can be used as scaffolds for the design and development of new antiplasmodial drugs.


Assuntos
Desenho de Fármacos , Testes de Sensibilidade Parasitária , Antimaláricos/síntese química , Antimaláricos/farmacologia , Pirimidinonas , Pirróis
16.
Autoimmunity ; 42(6): 545-52, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19657771

RESUMO

The acquisition of protective immunity in malaria is a slow process during which autoantibodies are produced. The present work aimed at studying a possible interference of autoimmune responses on malaria immune protection. This was done by investigating the presence of autoantibodies in the sera of malarious patients, by searching for reactivity of autoantibodies from autoimmune patients against plasmodial antigens, and by studying the effect of such antibodies on the in vitro growth of Plasmodium falciparum. Sera from systemic lupus erythematosus (SLE) and malaria patients were tested against autologous and plasmodial antigens. Out of the 109 SLE sera tested, 48 (44%) reacted against the parasite. In addition, 26 (47%) out of 55 randomly selected sera, mainly those containing anti-DNA and antinuclear autoantibodies, were able to inhibit parasite growth to some extent. Conversely, a high frequency (81%) of sera of malaria patients exhibited reactivity against autoantigens. The results show that patients with autoimmune processes can produce antibodies that recognize plasmodial antigens in the absence of plasmodial infection, that malaria patients can produce autoantibodies, that SLE sera can inhibit plasmodial growth in vitro, and that the presence of anti-DNA and antinuclear antibodies may be important in such anti-plasmodial activity. It is concluded that autoimmune responses may have influence on the protective immunity against malaria.


Assuntos
Antígenos de Protozoários/imunologia , Autoanticorpos/imunologia , Soros Imunes/imunologia , Lúpus Eritematoso Sistêmico/sangue , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/imunologia , Animais , Antígenos de Protozoários/metabolismo , Autoanticorpos/farmacologia , Reações Cruzadas , Humanos , Soros Imunes/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Plasmodium falciparum/crescimento & desenvolvimento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA