Discovery of 1,2,4-oxadiazole derivatives as a novel class of noncompetitive inhibitors of 3-hydroxykynurenine transaminase (HKT) from Aedes aegypti

Maciel, Larissa G.; Oliveira, Andrew A.; Romão, Tatiany Patrícia; Leal, Laylla L.L.; Güido, Rafael Victório Carvalho; Silva-Filha, Maria Helena Neves Lobo; Anjos, Janaína V. dos; Soares, Thereza A.

doi:10.1016/j.bmc.2019.115252

Cited by 13 publications

(19 citation statements)

References 67 publications

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“…To overcome this issue, these solutions must be freshly prepared and stocked at low temperatures even during the experiments. Another drawback could be the pH evaluation above 9, as mentioned in our previous work [5] . The conditions described here prevent the formation of insoluble Fe 3+ species which lead to anomalous absorbances and/or false positives.…”

Section: Discussionmentioning

confidence: 93%

“…The conditions described here prevent the formation of insoluble Fe 3+ species which lead to anomalous absorbances and/or false positives. However, these extreme values of pHs are not the common optimal pH for HKT enzymes [5 , 7] . To the best of our knowledge, this is the fastest and cheapest method of screening for new HKT inhibitors ever reported, with an actual cost per sample 7 times smaller than the previous HPLC-based methodology.…”

Section: Discussionmentioning

confidence: 94%

“…The estimation of the kinetics constants can be performed by adjusting the amount (or volume) of 3-HK, Pyruvate and Buffer solutions in Mix 2. In these experiments, we tested four different 3-HK concentrations (0.5, 2.0, 4.0 and 8.5 mM) to determine the kinetics constants [5] ( Fig. 2 E).…”

Section: Enzyme Kineticsmentioning

confidence: 99%

“…In this pathway, tryptophan is oxidized to quinolinic or kynurenic acid or xanthurenic acid (XA) depending on the organism. In mosquitoes, the chemically stable XA is biosynthesized from 3-hydroxykynurenine in a process catalyzed by 3-hydroxykynurenine transaminase (HKT), the sole enzyme responsible for 3-HK regulation in mosquitoes [5] , [6] , [7] , [8] . Therefore, the inhibition of the enzymatic conversion of 3-HK into xanthurenic acid provides in a powerful approach to control A. aegypti development via the accumulation of 3-HK, a toxic metabolite to living organisms, since it can be spontaneously oxidized into reactive oxygen species, leading to oxidative stress in mosquito's neuronal cells [4] .…”

Section: Introductionmentioning

confidence: 99%

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Fast and low-cost evaluation of hydroxykynurenine activity

2020

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The enzyme 3-hydroxykynurenine transaminase (HKT) acts as an important enzyme in tryptophan catabolism of disease-carrier insects, e.g. Aedes aegypti and Anopheles gambiae . HKT is a detoxification enzyme that converts 3-hydroxykynurenine (a precursor for reactive nitrogen and oxygen species) into xanthurenic acid (stable and nontoxic compound). We have previously synthesized eleven new oxadiazole derivatives and demonstrated their noncompetitive inhibitory activity towards HKT from A. aegypti (https://doi.org/10.1016/j.bmc.2019.115252). These findings are presented in a research paper accompanying the present technical report on a new assay to overcome the fact that the substrate and product of the HKT-catalyzed reaction exhibit maximum absorption at very near wavelength (370 and 369 nm, respectively). The methods previously described in the literature rely on chromatographic separation prior to absorbance quantification, which limits their use for inhibitor screening. Due to HKT attractive features as a molecular target for larvicidal compounds, we report herein a new, faster and affordable methodology to evaluate the enzymatic activity of recombinant HKT, and therefore allow for the fast screening of potential HKT inhibitors via absorbance spectrophotometer. The advantages of the proposed methodology to previously described ones are: It is faster and cheaper than HPLC-based assays because it does not require the use of chromatography columns and solvents to separate reaction components; It uses of 96-well plates, enabling the simultaneous quantification of samples; It can be applied to all transaminases that have xanthurenic acid as a product.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Section: Enzyme Kineticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fast and low-cost evaluation of hydroxykynurenine activity

2020

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“…3HKT has been observed to be the target for 1,2,4-oxadiazole compounds having larvicidal activity against Ae. aegypti [191,192]. Since 3HKT of An.…”

Section: Role Of Metabolic Proteins In Plasmodium Parasite Developmentmentioning

confidence: 99%

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

et al. 2020

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The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an effective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identification of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmission exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specificity can yield insecticides with no significant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will significantly help to curb malaria transmission.

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Luminescent Supramolecular Metallogels: Drug Loading and Eu(III) as Structural Probe

Freire,

Coelho,

Maciel

et al. 2024

Chemistry A European J

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Supramolecular metallogels combine the rheological properties of gels with the color, magnetism, and other properties of metal ions. Lanthanide ions such as Eu(III) can be valuable components of metallogels due to their fascinating luminescence. In this work, we combine Eu(III) and iminodiacetic acid (IDA) into luminescent hydrogels. We investigate the tailoring of the rheological properties of these gels by changes in their metal:ligand ratio. Further, we use the highly sensitive Eu(III) luminescence to obtain information about the chemical structure of the materials. In special, we take advantage of computational calculations to employ an indirect method for structural elucidation, in which the simulated luminescent properties of candidate structures are matched to the experimental data. With this strategy, we can propose molecular structures for different EuIDA gels. We also explore the usage of these gels for the loading of bioactive molecules such as OXA, observing that its aldose reductase activity remains present in the gel. We envision that the findings from this work could inspire the development of luminescent hydrogels with tunable rheology for applications such as 3D printing and imaging‐guided drug delivery platforms. Finally, Eu(III) emission‐based structural elucidation could be a powerful tool in the characterization of advanced materials.

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Discovery of 1,2,4-oxadiazole derivatives as a novel class of noncompetitive inhibitors of 3-hydroxykynurenine transaminase (HKT) from Aedes aegypti

Cited by 13 publications

References 67 publications

Fast and low-cost evaluation of hydroxykynurenine activity

Fast and low-cost evaluation of hydroxykynurenine activity

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

Luminescent Supramolecular Metallogels: Drug Loading and Eu(III) as Structural Probe

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