Selective and Irreversible Inhibitors of Mosquito Acetylcholinesterases for Controlling Malaria and Other Mosquito-Borne Diseases

New insecticides are urgently needed because resistance to current insecticides allows resurgence of disease-transmitting mosquitoes while concerns for human toxicity from current compounds are growing. We previously reported the finding of a free cysteine (Cys) residue at the entrance of the active site of acetylcholinesterase (AChE) in some insects but not in mammals, birds, and fish. These insects have two AChE genes (AP and AO), and only AP-AChE carries the Cys residue. Most of these insects are disease vectors such as the African malaria mosquito (Anopheles gambiae sensu stricto) or crop pests such as aphids. Recently we reported a Cys-targeting small molecule that irreversibly inhibited all AChE activity extracted from aphids while an identical exposure caused no effect on the human AChE. Full inhibition of AChE in aphids indicates that AP-AChE contributes most of the enzymatic activity and suggests that the Cys residue might serve as a target for developing better aphicides. It is therefore worth investigating whether the Cys-targeting strategy is applicable to mosquitocides. Herein, we report that, under conditions that spare the human AChE, a methanethiosulfonate-containing molecule at 6 µM irreversibly inhibited 95% of the AChE activity extracted from An. gambiae s. str. and >80% of the activity from the yellow fever mosquito (Aedes aegypti L.) or the northern house mosquito (Culex pipiens L.) that is a vector of St. Louis encephalitis. This type of inhibition is fast (∼30 min) and due to conjugation of the inhibitor to the active-site Cys of mosquito AP-AChE, according to our observed reactivation of the methanethiosulfonate-inhibited AChE by 2-mercaptoethanol. We also note that our sulfhydryl agents partially and irreversibly inhibited the human AChE after prolonged exposure (>4 hr). This slow inhibition is due to partial enzyme denaturation by the inhibitor and/or micelles of the inhibitor, according to our studies using atomic force microscopy, circular dichroism spectroscopy, X-ray crystallography, time-resolved fluorescence spectroscopy, and liquid chromatography triple quadrupole mass spectrometry. These results support our view that the mosquito-specific Cys is a viable target for developing new mosquitocides to control disease vectors and to alleviate resistance problems with reduced toxicity toward non-target species

Diagnóstico e tratamento das anemias carenciais na gestação: consensos e controvérsias Diagnosis and treatment of nutritional anemia in pregnancy: consensus and controversies

A anemia por carência de ferro representa a deficiência nutricional de maior prevalência em todo o mundo. A mulher e a criança são os grupos biológicos mais vulneráveis. Embora seja um dos procedimentos terapêuticos mais antigos da prática médica, o tratamento das anemias carenciais não está devidamente consolidado na rotina dos serviços de saúde. Em conseqüência, a eficácia do tratamento, os esquemas de tratamento, as recomendações posológicas, a adesão das pacientes e os critérios de acompanhamento são pontos cruciais na avaliação das propostas de intervenção a serem implementadas.<br>The iron-deficiency anemia represents the nutritional disorder of higher prevalence in the whole world. The woman and child are the groups more vulnerable. Although the treatment of the anemia is one of the oldest therapeutic, this procedure is not entirely established in the routine of the health services. Therefore, the effectiveness of the treatments, the different schemes, the posology recommendations, the adhesion of the patients to the treatment and the follow-up criteria are essential points in the evaluation of proposed interventions