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1.
Antiviral Res ; 220: 105753, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37967754

RESUMO

Dengue infection is a global health problem as climate change facilitates the spread of mosquito vectors. Infected patients could progress to severe plasma leakage and hemorrhagic shock, where current standard treatment remains supportive. Previous reports suggested that several flavonoid derivatives inhibited mosquito-borne flaviviruses. This work aimed to explore sulfonamide chalcone derivatives as dengue inhibitors and to identify molecular targets. We initially screened 27 sulfonamide chalcones using cell-based antiviral and cytotoxic screenings. Two potential compounds, SC22 and SC27, were identified with DENV1-4 EC50s in the range of 0.71-0.94 and 3.15-4.46 µM, and CC50s at 14.63 and 31.02 µM, respectively. The compounds did not show any elevation in ALT or Cr in C57BL/6 mice on the 1st, 3rd, and 7th days after being administered intraperitoneally with 50 mg/kg SC22 or SC27 in a single dose. Moreover, the SAM-binding site of NS5 methyltransferase was a potential target of SC27 identified by computational and enzyme-based assays. The main target of SC22 was in a late stage of viral replication, but the exact target molecule had yet to be identified. In summary, a sulfonamide chalcone, SC27, was a potential DENV inhibitor that targeted viral methyltransferase. Further investigation should be the study of the structure-activity relationship of SC27 derivatives for higher potency and lower toxicity.


Assuntos
Chalcona , Chalconas , Vírus da Dengue , Dengue , Humanos , Animais , Camundongos , Vírus da Dengue/química , Chalcona/farmacologia , Chalcona/uso terapêutico , Chalconas/farmacologia , Metiltransferases , Camundongos Endogâmicos C57BL , Sítios de Ligação , Dengue/tratamento farmacológico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Antivirais/uso terapêutico , Proteínas não Estruturais Virais , Replicação Viral
2.
Emerg Microbes Infect ; 12(2): 2270074, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37842770

RESUMO

Chikungunya virus is a re-emerging arbovirus that has caused epidemic outbreaks in recent decades. Patients in older age groups with high viral load and severe immunologic response during acute infection are likely to develop chronic arthritis and severe joint pain. Currently, no antiviral drug is available. Previous studies suggested that a flavone derivative, 8-bromobaicalein, was a potential dengue and Zika replication inhibitor in a cell-based system targeting flaviviral polymerase. Here we characterized that 8-bromobaicalein inhibited chikungunya virus replication with EC50 of 0.49 ± 0.11 µM in Vero cells. The molecular target predicted at viral nsP1 methyltransferase using molecular binding and fragment molecular orbital calculation. Additionally, oral administration of 250 mg/kg twice daily treatment alleviated chikungunya-induced musculoskeletal inflammation and reduced viral load in healthy adult mice. Pharmacokinetic analysis indicated that the 250 mg/kg administration maintained the compound level above EC99.9 for 12 h. Therefore, 8-bromobaicalein should be a potential candidate for further development as a pan-arboviral drug.


Assuntos
Arbovírus , Febre de Chikungunya , Vírus Chikungunya , Infecção por Zika virus , Zika virus , Chlorocebus aethiops , Humanos , Adulto , Animais , Camundongos , Idoso , Febre de Chikungunya/tratamento farmacológico , Células Vero , Carga Viral , Vírus Chikungunya/fisiologia , Inflamação
4.
Sci Rep ; 13(1): 4891, 2023 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-36966240

RESUMO

Dengue and Zika viruses are mosquito-borne flaviviruses burdening millions every year with hemorrhagic fever and neurological symptoms. Baicalein was previously reported as a potential anti-flaviviral candidate and halogenation of flavones and flavanones potentiated their antiviral efficacies. Here, we reported that a chemically modified 8-bromobaicalein effectively inhibited all dengue serotypes and Zika viruses at 0.66-0.88 micromolar in cell-based system. The compound bound to dengue serotype 2 conserved pocket and inhibited the dengue RdRp activity with 6.93 fold more than the original baicalein. Moreover, the compound was mildly toxic against infant and adult C57BL/6 mice despite administering continuously for 7 days. Therefore, the 8-bromobaicalein should be investigated further in pharmacokinetics and efficacy in an animal model.


Assuntos
Vírus da Dengue , Dengue , Flavivirus , Infecção por Zika virus , Zika virus , Animais , Camundongos , Dengue/tratamento farmacológico , Camundongos Endogâmicos C57BL
5.
Molecules ; 28(3)2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36770642

RESUMO

Dengue is a mosquito-borne flavivirus that causes 21,000 deaths annually. Depsides and depsidones of lichens have previously been reported to be antimicrobials. In this study, our objective was to identify lichen-derived depsides and depsidones as dengue virus inhibitors. The 18 depsides and depsidones of Usnea baileyi, Usnea aciculifera, Parmotrema dilatatum, and Parmotrema tsavoense were tested against dengue virus serotype 2. Two depsides and one depsidone inhibited dengue virus serotype 2 without any apparent cytotoxicity. Diffractaic acid, barbatic acid, and Parmosidone C were three active compounds further characterized for their efficacies (EC50), cytotoxicities (CC50), and selectivity index (SI; CC50/EC50). Their EC50 (SI) values were 2.43 ± 0.19 (20.59), 0.91 ± 0.15 (13.33), and 17.42 ± 3.21 (8.95) µM, respectively. Diffractaic acid showed the highest selectivity index, and similar efficacies were also found in dengue serotypes 1-4, Zika, and chikungunya viruses. Cell-based studies revealed that the target was mainly in the late stage with replication and the formation of infectious particles. This report highlights that a lichen-derived diffractaic acid could become a mosquito-borne antiviral lead as its selectivity indices ranged from 8.07 to 20.59 with a proposed target at viral replication.


Assuntos
Dengue , Líquens , Infecção por Zika virus , Zika virus , Animais , Humanos , Depsídeos/farmacologia , Replicação Viral , Dengue/tratamento farmacológico
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