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1.
BMC Complement Med Ther ; 21(1): 64, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588819

RESUMO

BACKGROUND: The disparity of harvesting locations can influence the chemical composition of a plant species, which could affect its quality and bioactivity. Terminalia albida is widely used in traditional Guinean medicine whose activity against malaria has been validated in vitro and in murine models. The present work investigated the antimalarial properties and chemical composition of two samples of T. albida collected from different locations in Guinea. METHOD: T. albida samples were collected in different locations in Guinea, in Dubréka prefecture (West maritime Guinea) and in Kankan prefecture (eastern Guinea). The identity of the samples was confirmed by molecular analysis. In vitro antiplasmodial activity of the two extracts was determined against the chloroquine resistant strain PfK1. In vivo, extracts (100 mg/kg) were tested in two experimental murine models, respectively infected with P. chabaudi chabaudi and P. berghei ANKA. The chemical composition of the two samples was assessed by ultra-high-performance liquid chromatography coupled to high resolution mass spectrometry. RESULTS: In vitro, the Dubréka sample (TaD) was more active with an IC50 of 1.5 µg/mL versus 8.5 µg/mL for the extract from Kankan (TaK). In vivo, the antiparasitic effect of TaD was substantial with 56% of parasite inhibition at Day 10 post-infection in P. chabaudi infection and 61% at Day 8 in P. berghei model, compared to 14 and 19% inhibition respectively for the treatment with TaK. In addition, treatment with TaD further improved the survival of P. berghei infected-mice by 50% at Day 20, while the mortality rate of mice treated with Tak was similar to the untreated group. The LC/MS analysis of the two extracts identified 38 compounds, 15 of which were common to both samples while 9 and 14 other compounds were unique to TaD and TaK respectively. CONCLUSION: This study highlights the variability in the chemical composition of the species T. albida when collected in different geographical locations. These chemical disparities were associated with variable antimalarial effects. From a public health perspective, these results underline the importance of defining chemical fingerprints related to botanical species identification and to biological activity, for the plants most commonly used in traditional medicine.


Assuntos
Antimaláricos/química , Malária/tratamento farmacológico , Fitoterapia , Extratos Vegetais/química , Plasmodium/efeitos dos fármacos , Terminalia/química , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Feminino , Guiné , Malária/parasitologia , Masculino , Medicina Tradicional Africana , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Especificidade da Espécie , Terminalia/classificação
2.
Trends Parasitol ; 36(11): 884-887, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32771284

RESUMO

Resistance to the artemisinin derivatives, our most effective antimalarial drugs, has not manifest as a classical resistance phenotype in which parasites can tolerate higher drug concentrations. Instead, resistant parasites have an altered maturation. We hypothesize that the short half-life of artemisinin concentrations is an unanticipated driver of this novel resistance phenotype.


Assuntos
Artemisininas/farmacologia , Resistência a Medicamentos , Plasmodium/efeitos dos fármacos , Seleção Genética/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Humanos , Concentração Inibidora 50
3.
Parasitol Res ; 119(10): 3503-3515, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772176

RESUMO

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.


Assuntos
Amino Álcoois/farmacologia , Antiprotozoários/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Babesia/efeitos dos fármacos , Babesia/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Modelos Animais de Doenças , Leishmania/efeitos dos fármacos , Leishmania/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Plasmodium/efeitos dos fármacos , Plasmodium/crescimento & desenvolvimento , Infecções por Protozoários/tratamento farmacológico , Infecções por Protozoários/parasitologia , Resultado do Tratamento , Trypanosoma/efeitos dos fármacos , Trypanosoma/crescimento & desenvolvimento , Células Vero
4.
Cytometry A ; 97(9): 872-881, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32686260

RESUMO

Malaria is a threat to human mankind and kills about half a million people every year. On the other hand, COVID-19 resulted in several hundred thousand deaths since December 2019 and remains without an efficient and safe treatment. The antimalarials chloroquine (CQ) and its analog, hydroxychloroquine (HCQ), have been tested for COVID-19 treatment, and several conflicting evidence has been obtained. Therefore, the aim of this review was to summarize the evidence regarding action mechanisms of these compounds against Plasmodium and SARS-CoV-2 infection, together with cytometry applications. CQ and HCQ act on the renin angiotensin system, with possible implications on the cardiorespiratory system. In this context, flow and image cytometry emerge as powerful technologies to investigate the mechanism of therapeutic candidates, as well as for the identification of the immune response and prognostics of disease severity. Data from the large randomized trials support the conclusion that CQ and HCQ do not provide any clinical improvements in disease severity and progression of SARS-CoV-2 patients, as well as they do not present any solid evidence of increased serious side effects. These drugs are safe and effective antimalarials agents, but in SARS-CoV-2 patients, they need further studies in the context of clinical trials. © 2020 International Society for Advancement of Cytometry.


Assuntos
Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Animais , Antimaláricos/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Cloroquina/efeitos adversos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citometria de Fluxo , Interações entre Hospedeiro e Microrganismos , Interações Hospedeiro-Parasita , Humanos , Malária/diagnóstico , Malária/imunologia , Malária/parasitologia , Pandemias , Plasmodium/imunologia , Plasmodium/patogenicidade , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Resultado do Tratamento
6.
Trends Parasitol ; 36(9): 735-744, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32586776

RESUMO

Artemisinin and its derivatives (ART) are crucial first-line antimalarial drugs that rapidly clear parasitemia, but recrudescences of the infection frequently follow ART monotherapy. For this reason, ART must be used in combination with one or more partner drugs that ensure complete cure. The ability of malaria parasites to survive ART monotherapy may relate to an innate growth bistability phenomenon whereby a fraction of the drug-exposed population enters into metabolic quiescence (dormancy) as persister forms. Characterization of the events that underlie entry and waking from persistence may lead to lasting breakthroughs in malaria chemotherapy that can prevent recrudescences and protect the future of ART-based combination therapies.


Assuntos
Artemisininas/farmacologia , Resistência a Medicamentos , Plasmodium/efeitos dos fármacos , Antimaláricos/farmacologia , Humanos , Recidiva
7.
Trends Parasitol ; 36(6): 533-544, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32359872

RESUMO

Artemisinins - the frontline antimalarial drug class - are compromised by emerging resistance, putting at risk the lives of hundreds of thousands of people each year. Resistance is associated with mutations in a malaria parasite protein, called Kelch 13 (K13). Recent work suggests that K13 is located at the cytostome (cell mouth) that the parasite uses to take up hemoglobin. Here we explore the proposal that K13 mutations confer artemisinin resistance by dampening hemoglobin endocytosis. This model suggests that the resultant decrease in hemoglobin-derived heme reduces artemisinin activation, which is sufficient to enable parasite survival in the early ring stage of infection. A fuller understanding of the resistance mechanism will underpin efforts to develop alternative antimalarial strategies.


Assuntos
Artemisininas/farmacologia , Resistência a Medicamentos/genética , Plasmodium/efeitos dos fármacos , Plasmodium/genética , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Antimaláricos/farmacologia , Heme/metabolismo , Humanos , Mutação , Plasmodium/metabolismo
8.
Trends Parasitol ; 36(6): 520-532, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32340866

RESUMO

Endocytosis is critical for many functions in eukaryotic cells. Uptake of host cell cytosol, an indispensable endocytic process in malaria blood-stage parasites, has been known for a long time. However, it is only recently that the proteins involved in this process have started to emerge. Unexpectedly, some of these proteins revealed a critical role for endocytosis in artemisinin resistance. More recently, endocytosis was discovered in both intracellular and extracellular Toxoplasma gondii parasites. Here, we review these findings, compare the endolysosomal systems of Toxoplasma and Plasmodium parasites, and present current knowledge about endocytic mechanisms in apicomplexans.


Assuntos
Endocitose/fisiologia , Plasmodium/fisiologia , Toxoplasma/fisiologia , Animais , Antiparasitários/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos , Humanos , Plasmodium/efeitos dos fármacos , Toxoplasma/efeitos dos fármacos
9.
Malar J ; 19(1): 68, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046739

RESUMO

Malaria is major public health concerns which continues to claim the lives of more than 435,000 people each year. The challenges with anti-malarial drug resistance and detection of low parasitaemia forms an immediate barrier to achieve the fast-approaching United Nations Sustainable Development Goals of ending malaria epidemics by 2030. In this Opinion article, focusing on the recent published technologies, in particularly the nuclear magnetic resonance (NMR)-based diagnostic technologies, the authors offer their perspectives and highlight ways to bring these point-of-care technologies towards personalized medicine. To this end, they advocate an open sourcing initiative to rapidly close the gap between technological innovations and field implementation.


Assuntos
Hemeproteínas/análise , Espectroscopia de Ressonância Magnética/métodos , Malária/diagnóstico , Testes Imediatos , Medicina de Precisão/métodos , Animais , Resistência a Medicamentos , Hemeproteínas/química , Hemeproteínas/metabolismo , Humanos , Malária/epidemiologia , Malária/parasitologia , Fenótipo , Plasmodium/classificação , Plasmodium/efeitos dos fármacos , Plasmodium/genética , Sensibilidade e Especificidade
10.
Malar J ; 19(1): 16, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931813

RESUMO

BACKGROUND: The aim of this systematic review was to identify predictors of actual or intended adherence with malaria chemoprophylaxis amongst travellers from non-endemic countries visiting endemic countries. METHODS: A systematic review of the literature was conducted using MEDLINE, Embase, PsycINFO and Global Health databases for studies published up to April 2019. Studies were included if they assessed reasons for adherence among people travelling from a country where malaria was not endemic to a country where it was. RESULTS: Thirty-two studies were included. Predictors of adherence were categorized as relating to either the nature of the travel or the traveller themselves. The three main predictors associated with nature of travel included: destination (e.g. country visited, urban vs rural areas), length of travel and type of travel (e.g. package vs backpacking holiday). The four main traveller-associated predictors were: age, reason for travel (e.g. business, leisure or visiting friends and relatives), perceived risk of catching malaria and experienced or expected medication effects. CONCLUSIONS: In order to improve adherence, clinicians should focus on travellers who are least likely to exhibit adherent behaviour. This includes travellers visiting destinations known to have lower adherence figures (such as rural areas), backpackers, business travellers, younger travellers and those travelling for longer periods of time. They should also check to ensure travellers' perceptions of the risks of malaria are realistic. Where appropriate, misperceptions (such as believing that curing malaria is easier than taking prophylaxis or that travellers visiting relatives have some level of innate immunity) should be corrected. All travellers should be informed of the potential side-effects of medication and given guidance on why it is nonetheless beneficial to continue to take prophylaxis. Further research is required to test interventions to improve adherence.


Assuntos
Antimaláricos/uso terapêutico , Doenças Endêmicas/prevenção & controle , Malária/prevenção & controle , Adesão à Medicação , Viagem , Fatores Etários , Animais , Anopheles/parasitologia , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Escolaridade , Humanos , Malária/tratamento farmacológico , Malária/transmissão , Mosquitos Vetores/parasitologia , Motivação , Plasmodium/efeitos dos fármacos , Plasmodium/patogenicidade , Plasmodium/fisiologia , Fatores de Risco , População Rural , Fatores Socioeconômicos , Fatores de Tempo
11.
Biomed Res Int ; 2020: 6135696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31993450

RESUMO

Malaria is one of the life-threatening diseases in the world. The spread of resistance to antimalarial drugs is a major challenge, and resistance to artemisinin has been reported in the Southeast Asian region. In the previous study, the active compound of Streptomyces hygroscopicus subsp. Hygroscopicus (S. hygroscopicus), eponemycin, has been shown to have antimalarial effects. To further analyze the effects of other active compounds on the Plasmodium parasite, identifying and analyzing the effectiveness of compounds contained in S. hygroscopicus through instrumentation of liquid chromatography/mass spectrometry (LC/MS) and in silico studies were very useful. This study aimed at identifying other derivative compounds from S. hygroscopicus and screening the antimalarial activity of the compound by assessing the binding affinity, pharmacokinetic profile, and bond interaction. The derivative compounds were identified using LC/MS. Protein targets for derivative compounds were found through literature studies, and the results of identification of compounds and protein targets were reconstructed into three-dimensional models. Prediction of pharmacokinetic profiles was carried out using Swiss ADME. Screening of protein targets for the derivative compound was carried out using the reverse molecular docking method. Analyzing bond interaction was done by LigPlot. One compound from S. hygroscopicus, i.e., 6,7-dinitro-2-[1, 2, 4]triazole-4-yl-benzo[de]isoquinoline-1,3-dione, was successfully identified using LC/MS. This compound was an isoquinoline derivative compound. Through literature studies with inclusion criteria, thirteen protein targets were obtained for reverse molecular docking. This isoquinoline derivative had the potential to bind to each protein target. The pharmacokinetic profile showed that this compound had the drug-likeness criteria. Conclusion. 6,7-Dinitro-2-[1, 2, 4]triazole-4-yl-benzo[de]isoquinoline-1,3-dione has antimalarial activity as shown by reverse molecular docking studies and pharmacokinetic profiles. The best inhibitory ability of compounds based on bond affinity is with adenylosuccinate synthetase.


Assuntos
Antimaláricos/uso terapêutico , Isoquinolinas/uso terapêutico , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Streptomyces/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacocinética , Isoquinolinas/isolamento & purificação , Isoquinolinas/farmacocinética , Ligantes , Malária/parasitologia , Simulação de Acoplamento Molecular
12.
Nucleic Acids Res ; 48(D1): D1006-D1021, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31691834

RESUMO

The IUPHAR/BPS Guide to PHARMACOLOGY (www.guidetopharmacology.org) is an open-access, expert-curated database of molecular interactions between ligands and their targets. We describe significant updates made over the seven releases during the last two years. The database is notably enhanced through the continued linking of relevant pharmacology with key immunological data types as part of the IUPHAR Guide to IMMUNOPHARMACOLOGY (www.guidetoimmunopharmacology.org) and by a major new extension, the IUPHAR/MMV Guide to Malaria PHARMACOLOGY (www.guidetomalariapharmacology.org). The latter has been constructed in partnership with the Medicines for Malaria Venture, an organization dedicated to identifying, developing and delivering new antimalarial therapies that are both effective and affordable. This is in response to the global challenge of over 200 million cases of malaria and 400 000 deaths worldwide, with the majority in the WHO Africa Region. It provides new pharmacological content, including molecular targets in the malaria parasite, interaction data for ligands with antimalarial activity, and establishes curation of data from screening assays, used routinely in antimalarial drug discovery, against the whole organism. A dedicated portal has been developed to provide quick and focused access to these new data.


Assuntos
Antimaláricos/farmacologia , Bases de Dados Factuais , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas/métodos , Farmacologia , Antimaláricos/uso terapêutico , Humanos , Ligantes , Malária/tratamento farmacológico , Malária/parasitologia , Terapia de Alvo Molecular , Plasmodium/efeitos dos fármacos , Software , Interface Usuário-Computador , Navegador
13.
Curr Top Med Chem ; 20(2): 140-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31702503

RESUMO

INTRODUCTION: Structural modulation of previously identified lead spiro-ß-lactams with antimicrobial activity was carried out. OBJECTIVE: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. METHODS: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-ß-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. RESULTS: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied ß- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. CONCLUSION: The designed structural modulation of biologically active spiro-ß-lactams involved the replacement of the four-membered ß-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between ß- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the ß-lactamic core is a requirement for the activity against both HIV and Plasmodium.


Assuntos
Fármacos Anti-HIV/farmacologia , Antiprotozoários/farmacologia , HIV/efeitos dos fármacos , Lactamas/farmacologia , Plasmodium/efeitos dos fármacos , Compostos de Espiro/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Lactamas/síntese química , Lactamas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Testes de Sensibilidade Parasitária , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
14.
Trends Parasitol ; 36(2): 85-87, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31883707

RESUMO

A recent report by Jennison et al. reveals an important role for plasmepsin V (PMV), an aspartyl protease, in the development of malaria transmission stages. The authors showed that PMV activity is critical for protein export in these stages and that specific PMV inhibitors block parasite transmission to mosquitoes.


Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Malária/parasitologia , Malária/transmissão , Plasmodium/enzimologia , Animais , Antimaláricos/farmacologia , Carbamatos/farmacologia , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Estágios do Ciclo de Vida/fisiologia , Malária/prevenção & controle , Oligopeptídeos/farmacologia , Plasmodium/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos
15.
J Med Chem ; 63(2): 591-600, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31850752

RESUMO

New drugs that target Plasmodium species, the causative agents of malaria, are needed. The enzyme N-myristoyltransferase (NMT) is an essential protein, which catalyzes the myristoylation of protein substrates, often to mediate membrane targeting. We screened ∼1.8 million small molecules for activity against Plasmodium vivax (P. vivax) NMT. Hits were triaged based on potency and physicochemical properties and further tested against P. vivax and Plasmodium falciparum (P. falciparum) NMTs. We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds with low selectivity indices. We identified 23 chemical classes specific for the inhibition of Plasmodium NMTs over human NMTs, including multiple novel scaffolds. Cocrystallization of P. vivax NMT with one compound revealed peptide binding pocket binding. Other compounds show a range of potential modes of action. Our data provide insight into the activity of a collection of selective inhibitors of Plasmodium NMT and serve as a starting point for subsequent medicinal chemistry efforts.


Assuntos
Aciltransferases/antagonistas & inibidores , Antimaláricos/síntese química , Antimaláricos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , Aciltransferases/química , Animais , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Malária/tratamento farmacológico , Modelos Moleculares , Plasmodium falciparum/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
16.
Malar J ; 18(1): 404, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805944

RESUMO

BACKGROUND: Malaria remains a significant public health challenge in regions of the world where it is endemic. An unprecedented decline in malaria incidences was recorded during the last decade due to the availability of effective control interventions, such as the deployment of artemisinin-based combination therapy and insecticide-treated nets. However, according to the World Health Organization, malaria is staging a comeback, in part due to the development of drug resistance. Therefore, there is an urgent need to discover new anti-malarial drugs. This article reviews the literature on natural products with antiplasmodial activity that was reported between 2010 and 2017. METHODS: Relevant literature was sourced by searching the major scientific databases, including Web of Science, ScienceDirect, Scopus, SciFinder, Pubmed, and Google Scholar, using appropriate keyword combinations. RESULTS AND DISCUSSION: A total of 1524 compounds from 397 relevant references, assayed against at least one strain of Plasmodium, were reported in the period under review. Out of these, 39% were described as new natural products, and 29% of the compounds had IC50 ≤ 3.0 µM against at least one strain of Plasmodium. Several of these compounds have the potential to be developed into viable anti-malarial drugs. Also, some of these compounds could play a role in malaria eradication by targeting gametocytes. However, the research into natural products with potential for blocking the transmission of malaria is still in its infancy stage and needs to be vigorously pursued.


Assuntos
Antimaláricos/farmacologia , Produtos Biológicos/farmacologia , Malária/prevenção & controle , Plasmodium/efeitos dos fármacos , Humanos
17.
Malar J ; 18(1): 430, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852480

RESUMO

BACKGROUND: Sulfadoxine-pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap. METHODS: Dried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays. RESULTS: Across populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5-25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3-87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7-47.2%). The dhfr I164L mutation was found in one sample. CONCLUSIONS: The prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DRC. K540E mutations regularly co-occurred with mutations in dhps A581G but not with the dhfr I164L mutation. The current results do not support implementation of IPTi with SP in the study area.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária/prevenção & controle , Plasmodium/efeitos dos fármacos , Pirimetamina/farmacologia , Sulfadoxina/farmacologia , Adolescente , Biomarcadores/sangue , Quimioprevenção/estatística & dados numéricos , Criança , Pré-Escolar , República Democrática do Congo , Combinação de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
18.
Dis Model Mech ; 12(12)2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31874839

RESUMO

Malaria is an infectious disease caused by parasitic protozoa in the Plasmodium genus. A complete understanding of the biology of these parasites is challenging in view of their need to switch between the vertebrate and insect hosts. The parasites are also capable of becoming highly motile and of remaining dormant for decades, depending on the stage of their life cycle. Malaria elimination efforts have been implemented in several endemic countries, but the parasites have proven to be resilient. One of the major obstacles for malaria elimination is the development of antimalarial drug resistance. Ineffective treatment regimens will fail to remove the circulating parasites and to prevent the local transmission of the disease. Genomic epidemiology of malaria parasites has become a powerful tool to track emerging drug-resistant parasite populations almost in real time. Population-scale genomic data are instrumental in tracking the hidden pockets of Plasmodium in nationwide elimination efforts. However, genomic surveillance data can be useful in determining the threat only when combined with a thorough understanding of the malarial resistome - the genetic repertoires responsible for causing and potentiating drug resistance evolution. Even though long-term selection has been a standard method for drug target identification in laboratories, its implementation in large-scale exploration of the druggable space in Plasmodium falciparum, along with genome-editing technologies, have enabled mapping of the genetic repertoires that drive drug resistance. This Review presents examples of practical use and describes the latest technology to show the power of real-time genomic epidemiology in achieving malaria elimination.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária/tratamento farmacológico , Malária/parasitologia , Plasmodium/efeitos dos fármacos , Plasmodium/genética , Animais , Culicidae , Erradicação de Doenças , Genômica , Humanos , Cooperação Internacional , Epidemiologia Molecular , Mutação , Plasmodium falciparum
19.
Trends Parasitol ; 35(12): 953-963, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31699532

RESUMO

Artemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2α. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure.


Assuntos
Artemisininas/farmacologia , Artemisininas/uso terapêutico , Resistência a Medicamentos/genética , Modelos Biológicos , Plasmodium/efeitos dos fármacos , Plasmodium/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Humanos , Malária/tratamento farmacológico , Mutação , Proteínas de Protozoários/genética
20.
Molecules ; 24(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766184

RESUMO

Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) Plasmodium falciparum clone strain and in vivo against Plasmodium berghei-infected mouse model. Among the quinoline derivatives, new hybrids between chloroquine and sulfadoxine were designed, which gave rise to an important prototype that was more active than both chloroquine and sulfadoxine. Hybrids between chloroquine-atorvastatin and primaquine-atorvastatin were also synthesized and shown to be more potent than the parent drugs alone. Additionally, among the quinoline derivatives, new mefloquine derivatives were synthesized. Among the non-quinoline derivatives, we obtained excellent results with the triazolopyrimidine nucleus, which gave us prototype I that inspired the synthesis of new heterocycles. The pyrazolopyrimidine derivatives stood out as non-quinoline derivatives that are potent inhibitors of the P. falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. We also examined the pyrazolopyridine and pyrazolopyrimidine nuclei.


Assuntos
Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Desenvolvimento de Medicamentos , Malária/tratamento farmacológico , Plasmodium/efeitos dos fármacos , Animais , Antimaláricos/química , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Malária/parasitologia , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/química , Piridinas/farmacologia , Piridinas/uso terapêutico , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/uso terapêutico
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