A second generation of 1,2,4-oxadiazole derivatives with enhanced solubility for inhibition of 3-hydroxykynurenine transaminase (HKT) from <i>Aedes aegypti</i>

Maciel, Larissa G.; Barbosa, Andrey S.; Filho, Edilson Beserra de Alencar; Soares, Thereza A.; Anjos, Janaína V. dos

doi:10.1039/d0md00305k

Cited by 8 publications

(9 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It also catalyzes the transamination of alanine with glyoxylate as an amino group acceptor, but less efficiently [ 10 , 13 ]. The detoxification function of the enzyme HKT over 3-HK makes HKT a potential insecticide target [ 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Biochemical Evolution of a Potent Target of Mosquito Larvicide, 3-Hydroxykynurenine Transaminase

et al. 2022

View full text Add to dashboard Cite

A specific mosquito enzyme, 3-hydroxykynurenine transaminase (HKT), is involved in the processing of toxic metabolic intermediates of the tryptophan metabolic pathway. The HKT enzymatic product, xanthurenic acid, is required for Plasmodium spp. development in the mosquito vectors. Therefore, an inhibitor of HKT may not only be a mosquitocide but also a malaria-transmission blocker. In this work, we present a study investigating the evolution of HKT, which is a lineage-specific duplication of an alanine glyoxylate aminotransferases (AGT) in mosquitoes. Synteny analyses, together with the phylogenetic history of the AGT family, suggests that HKT and the mosquito AGTs are paralogous that were formed via a duplication event in their common ancestor. Furthermore, 41 amino acid sites with significant evidence of positive selection were identified, which could be responsible for biochemical and functional evolution and the stability of conformational stabilization. To get a deeper understanding of the evolution of ligands’ capacity and the ligand-binding mechanism of HKT, the sequence and the 3D homology model of the common ancestor of HKT and AGT in mosquitoes, ancestral mosquito AGT (AncMosqAGT), were inferred and built. The homology model along with 3-hydroxykynurenine, kynurenine, and alanine were used in docking experiments to predict the binding capacity and ligand-binding mode of the new substrates related to toxic metabolites detoxification. Our study provides evidence for the dramatic biochemical evolution of the key detoxifying enzyme and provides potential sites that could hinder the detoxification function, which may be used in mosquito larvicide and design.

show abstract

Section: Introductionmentioning

confidence: 99%

Biochemical Evolution of a Potent Target of Mosquito Larvicide, 3-Hydroxykynurenine Transaminase

et al. 2022

View full text Add to dashboard Cite

show abstract

“…gambiae (AgHKT) . Previously, it was shown that AeHKT is inhibited by 1,2,4-oxadiazole derivatives with IC 50 values ranging from 35 to 340 μM via a noncompetitive mechanism. , In this work, we have investigated the binding free energies and dissociation kinetics of the complexes between the inhibitors 4-(2-aminophenyl)-4-oxobutyric acid (4OB) and sodium 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (OXA) and the enzymes AeHKT and AgHKT. We have found that OXA binds to both AeHKT and AgHKT enzymes with binding energies 2-fold more favorable than the crystallographic inhibitor 4OB.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, only 155 three-dimensional structures from mosquitoes were deposited in the Protein Data Bank until November 2022, attesting to the unexplored potential of insect proteins as drug targets for the control of vector-transmitted diseases. In this work, we solved the X-ray structure of AeHKT (PDB ID: 6MFB) to serve as a target for the discovery of new AeHKT inhibitors and optimization of 1,2,4-oxadiazole derivatives. − We have further performed a series of metadynamics (Meta-MD) simulations to compute the multidimensional free energy surface (FES) for the binding process between the two HKT enzymes (AeHKT, AgHKT) and two inhibitors: 4OB, previously cocrystallized in complex with AgHKT, and a canonical representative of the 1,2,4-oxadiazole derivatives, sodium 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (OXA) . Since 4OB is the sole HKT inhibitor for which the enzyme-inhibitor complex crystallographic data is available, it serves as the gold standard for validation of new inhibitors via structure-based approaches.…”

Section: Introductionmentioning

confidence: 99%

“…As part of a decade-long effort, we have identified a class of 1,2,4-oxadiazole derivatives with larvicidal activity against the A. aegypti mosquito and low toxicity in mammals. − Structural comparisons supported by computational calculations for the 1,2,4-oxadiazole nucleus against known inhibitors of different insect enzymes led to the identification of the enzyme 3-hydroxykynurenine transaminase (HKT) as a potential target for these larvicide prototypes with IC 50 values ranging from 35 to 340 μM. , HKT is a pyridoxal-5′-phosphate (PLP)-dependent enzyme responsible for the transamination of the toxic 3-hydroxykynurenine (3-HK) to the chemically stable xanthurenic acid (XA) in mosquito larvae and adults . This reaction is part of the main detoxification route regulating the degradation of tryptophan in mosquitoes .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of 3-Hydroxykynurenine Transaminase from Aedes aegypti and Anopheles gambiae: A Mosquito-Specific Target to Combat the Transmission of Arboviruses

Maciel

Ferraz

Oliveira

et al. 2023

ACS Bio Med Chem Au

Self Cite

View full text Add to dashboard Cite

Arboviral infections such as Zika, chikungunya, dengue, and yellow fever pose significant health problems globally. The population at risk is expanding with the geographical distribution of the main transmission vector of these viruses, the Aedes aegypti mosquito. The global spreading of this mosquito is driven by human migration, urbanization, climate change, and the ecological plasticity of the species. Currently, there are no specific treatments for Aedes -borne infections. One strategy to combat different mosquito-borne arboviruses is to design molecules that can specifically inhibit a critical host protein. We obtained the crystal structure of 3-hydroxykynurenine transaminase (AeHKT) from A. aegypti , an essential detoxification enzyme of the tryptophan metabolism pathway. Since AeHKT is found exclusively in mosquitoes, it provides the ideal molecular target for the development of inhibitors. Therefore, we determined and compared the free binding energy of the inhibitors 4-(2-aminophenyl)-4-oxobutyric acid (4OB) and sodium 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (OXA) to AeHKT and AgHKT from Anopheles gambiae , the only crystal structure of this enzyme previously known. The cocrystallized inhibitor 4OB binds to AgHKT with K i of 300 μM. We showed that OXA binds to both AeHKT and AgHKT enzymes with binding energies 2-fold more favorable than the crystallographic inhibitor 4OB and displayed a 2-fold greater residence time τ upon binding to AeHKT than 4OB. These findings indicate that the 1,2,4-oxadiazole derivatives are inhibitors of the HKT enzyme not only from A. aegypti but also from A. gambiae .

show abstract

“…The second generation of sodium 4-[3-aryl-1,2,4-oxadiazol-5-yl] propanoates has also been synthesized and examined. 67 According to QSAR analysis, shortening the chain has been proved to be beneficial for larvicidal activity. As an example, compound 27 displayed an IC 50 value of 42 ± 1 μM, indicating greater potency than the first-generation inhibitor 25 .…”

Section: 24-oxadiazole Derivatives With Pesticidal Activitymentioning

confidence: 99%

1,2,4-Oxadiazole as a potential scaffold in agrochemistry: a review

Zhong,

Wu,

et al. 2023

Org. Biomol. Chem.

View full text Add to dashboard Cite

show abstract

A second generation of 1,2,4-oxadiazole derivatives with enhanced solubility for inhibition of 3-hydroxykynurenine transaminase (HKT) from Aedes aegypti

Abstract: Water-soluble oxadiazole-based HKT inhibitor library, comprising a new class of compounds for control of Aedes aegypti dissemination, act as competitive HKT enzyme inhibitors, promoting accumulation of the toxic metabolite 3-hydroxykynurenine in insect organism.

Cited by 8 publications

References 47 publications

Biochemical Evolution of a Potent Target of Mosquito Larvicide, 3-Hydroxykynurenine Transaminase

Biochemical Evolution of a Potent Target of Mosquito Larvicide, 3-Hydroxykynurenine Transaminase

Inhibition of 3-Hydroxykynurenine Transaminase from Aedes aegypti and Anopheles gambiae: A Mosquito-Specific Target to Combat the Transmission of Arboviruses

1,2,4-Oxadiazole as a potential scaffold in agrochemistry: a review

Contact Info

Product

Resources

About