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1.
Curr Microbiol ; 81(11): 375, 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39317904

RESUMO

Herpes simplex virus (HSV) infections can occur throughout life, thereby allowing transmission to new hosts, with an impact on public health. Acyclovir remains the treatment of choice for these infections; however, an increase in resistant strains in recent years has been observed. In this study, the activity of a native Delonix regia galactomannan (NDr) against HSV-1 was investigated in vitro. NDr was characterized using infrared spectroscopy and NMR. Evaluation of cytotoxicity and the antiviral effect was determined, respectively, by MTT and plaque reduction assays. The NDr concentrations that inhibited cell viability (CC50) and viral infection (IC50) by 50% were above 2000 and 64 µg/mL, respectively. Thus, the polysaccharide showed a high selectivity index (> 31.25). When NDr was added at different stages of HSV-1 replication, a strong inhibitory effect was found by direct interaction with the virus (71-67%, virucidal effect) or previously with the cell, 6 h before infection (99.8-68.4%, prophylactic effect) at concentrations from 200 to 50 µg/mL. NDr showed similar effects in prophylactic 1 h (52%) and adsorption inhibition (55%) assays at 200 µg/mL. A reduction in the antiherpetic effect was observed after infection. These results suggest that NDr is effective in the early stages of HSV-1 infection and is a promising agent for controlling herpetic infections.


Assuntos
Antivirais , Galactose , Herpesvirus Humano 1 , Mananas , Sementes , Mananas/farmacologia , Mananas/química , Galactose/análogos & derivados , Galactose/farmacologia , Antivirais/farmacologia , Antivirais/química , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Animais , Chlorocebus aethiops , Células Vero , Sementes/química , Replicação Viral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Humanos , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia
2.
Future Microbiol ; 19(17): 1475-1488, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39268668

RESUMO

Aim: To search for potential inhibitors to homoserine dehydrogenase (HSD) in Paracoccidioides brasiliensis the causative agent of paracoccidioidomycosis, an infection with a high mortality rate in Brazil.Materials & methods: The enzyme was modeled and used in the virtual screening of the compounds. The library was first screened by the Autodock, in which 66 molecules were better ranked than substrate, and then, also evaluated by the Molegro and Gold programs.Results: The HS23 and HS87 molecules were selected in common by the three programs, and ADME/Tox evaluation indicates they are not toxic. The molecular dynamics of PbHSD bonded to ligands showed stable complexes until 50 ns. To validate the results, compounds were purchased for assays of minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), synergic profile with Amphotericin B (AmB) and cytotoxicity. The two molecules presented MIC of 32 µg/ml and MFC of 64 µg/ml against the P. brasiliensis (strain Pb18). They also showed synergistic activity with AmB and a lack of toxicity against Hela and Vero cell lines.Conclusion: These results suggest that the HS23 and HS87 are promising candidates as PbHSD inhibitors and may be used as hits for the development of new drugs against paracoccidioidomycosis.


[Box: see text].


Assuntos
Antifúngicos , Inibidores Enzimáticos , Homosserina Desidrogenase , Testes de Sensibilidade Microbiana , Paracoccidioides , Paracoccidioides/efeitos dos fármacos , Paracoccidioides/enzimologia , Antifúngicos/farmacologia , Antifúngicos/química , Humanos , Homosserina Desidrogenase/antagonistas & inibidores , Homosserina Desidrogenase/metabolismo , Homosserina Desidrogenase/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Animais , Células Vero , Chlorocebus aethiops , Simulação de Acoplamento Molecular , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/microbiologia , Células HeLa , Brasil , Anfotericina B/farmacologia , Simulação de Dinâmica Molecular , Simulação por Computador , Sinergismo Farmacológico , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/química
3.
Int J Mol Sci ; 25(18)2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39337305

RESUMO

Graphene nanoplatelets (UGZ-1004) are emerging as a promising biomaterial in regenerative medicine. This study comprehensively evaluates UGZ-1004, focusing on its physical properties, cytotoxicity, intracellular interactions, and, notably, its effects on mesenchymal stem cells (MSCs). UGZ-1004 was characterized by lateral dimensions and layer counts consistent with ISO standards and demonstrated a high carbon purity of 0.08%. Cytotoxicity assessments revealed that UGZ-1004 is non-toxic to various cell lines, including 3T3 fibroblasts, VERO kidney epithelial cells, BV-2 microglia, and MSCs, in accordance with ISO 10993-5:2020/2023 guidelines. The study focused on MSCs and revealed that UGZ-1004 supports their gene expression alterations related to self-renewal and proliferation. MSCs exposed to UGZ-1004 maintained their characteristic surface markers. Importantly, UGZ-1004 promoted significant upregulation of genes crucial for cell cycle regulation and DNA repair, such as CDK1, CDK2, and MDM2. This gene expression profile suggests that UGZ-1004 can enhance MSC self-renewal capabilities, ensuring robust cellular function and longevity. Moreover, UGZ-1004 exposure led to the downregulation of genes associated with tumor development, including CCND1 and TFDP1, mitigating potential tumorigenic risks. These findings underscore the potential of UGZ-1004 to not only bolster MSC proliferation but also enhance their self-renewal processes, which are critical for effective regenerative therapies. The study highlights the need for continued research into the long-term impacts of graphene nanoplatelets and their application in MSC-based regenerative medicine.


Assuntos
Proliferação de Células , Grafite , Células-Tronco Mesenquimais , Proliferação de Células/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Animais , Grafite/química , Grafite/farmacologia , Camundongos , Chlorocebus aethiops , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Células Vero , Regulação da Expressão Gênica/efeitos dos fármacos , Nanopartículas/química , Linhagem Celular , Nanoestruturas/química
4.
Curr Microbiol ; 81(10): 343, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39227496

RESUMO

Chikungunya fever is a mosquito-borne disease caused by Chikungunya virus (CHIKV). Treatment of CHIKV infections is currently supportive and does not limit viral replication or symptoms of persistent chronic arthritis. Although there are multiple compounds reported as antivirals active against CHIKV in vitro, there are still no effective and safe antivirals. Thus, active research aims at the identification of new chemical structures with antiviral activity. Here, we report the screen of the Pandemic Response Box library of small molecules against a fully infectious CHIKV reporter virus. Our screening approach successfully identified previously reported CHIKV antiviral compounds within this library and further expanded potentially active hits, supporting the use of reporter-virus-based assays in high-throughput screening format as a reliable tool for antiviral drug discovery. Four molecules were identified as potential drug candidates against CHIKV: MMV1634402 (Brilacidin) and MMV102270 (Diphyllin), which were previously shown to present broad-spectrum antiviral activities, in addition to MMV1578574 (Eravacycline), and the antifungal MMV689401 (Fluopicolide), for which their antiviral potential is uncovered here.


Assuntos
Antivirais , Febre de Chikungunya , Vírus Chikungunya , Ensaios de Triagem em Larga Escala , Bibliotecas de Moléculas Pequenas , Vírus Chikungunya/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Humanos , Animais , Bibliotecas de Moléculas Pequenas/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Avaliação Pré-Clínica de Medicamentos , Replicação Viral/efeitos dos fármacos , Descoberta de Drogas , Chlorocebus aethiops , Células Vero
5.
Arch Microbiol ; 206(10): 406, 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39292269

RESUMO

Mayaro virus (MAYV) is the causative agent of Mayaro fever, which is characterized mainly by acute fever and long-term severe arthralgia, common manifestations of other arbovirus infections, making the correct diagnosis a challenge. Besides, MAYV infections have been reported in South America, especially in Brazil. However, the lack of vaccines or specific antiviral drugs to control these infections makes the search for new antivirals an urgent need. Herein, we evaluated the antiviral potential of synthetic ß-enaminoesters derivatives against MAYV replication and their pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico strategies. For this purpose, Vero cells were infected with MAYV at an MOI of 0.1, treated with compounds (50 µM) for 24 h, and virus titers were quantified by plaque reduction assays. Compounds 2b (83.33%) and 2d (77.53%) exhibited the highest activity with inhibition rates of 83.33% and 77.53%, respectively. The most active compounds 2b (EC50 = 18.92 µM; SI > 52.85), and 2d (EC50 = 14.52 µM; SI > 68.87) exhibited higher potency and selectivity than the control drug suramin (EC50 = 38.97 µM; SI > 25.66). Then, we investigated the mechanism of action of the most active compounds. None of the compounds showed virucidal activity, neither inhibited virus adsorption, but compound 2b inhibited virus entry (62.64%). Also, compounds 2b and 2d inhibited some processes involved with the release of new virus particles. Finally, in silico results indicated good ADMET parameters of the most active compounds and reinforced their promising profile as drug candidates against MAYV.


Assuntos
Alphavirus , Antivirais , Ésteres , Replicação Viral , Antivirais/farmacologia , Antivirais/química , Chlorocebus aethiops , Animais , Células Vero , Ésteres/farmacologia , Ésteres/química , Alphavirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Simulação por Computador , Brasil , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/virologia
6.
Viruses ; 16(9)2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39339832

RESUMO

Advances in diagnostic techniques coupled with ongoing environmental changes have resulted in intensified surveillance and monitoring of arbovirus circulation in the Amazon. This increased effort has resulted in increased detection of insect-specific viruses among hematophagous arthropods collected in the field. This study aimed to document the first isolation of Agua Salud alphavirus in mosquitoes collected within the Brazilian Amazon. Arthropods belonging to the family Culicidae were collected within a forest fragment located in the Environmental Protection Area of the metropolitan region of Belem. Subsequently, these specimens were meticulously identified to the species level. Afterward, the collected batches were macerated, and the resulting supernatant was then inoculated into C6/36 and Vero cell cultures to facilitate viral isolation. The presence of arboviruses within the inoculated cell cultures was determined through indirect immunofluorescence analysis. Furthermore, positive supernatant samples underwent nucleotide sequencing to precisely identify the viral strains present. Notably, a batch containing Culex (Melanoconion) mosquitoes was identified to be positive for the genus Alphavirus via indirect immunofluorescence. This study is the first report on insect-specific alphavirus isolation in Brazil and the first-ever description of Agua Salud alphavirus isolation within Amazon Forest remnants.


Assuntos
Alphavirus , Culex , Animais , Alphavirus/isolamento & purificação , Alphavirus/genética , Alphavirus/classificação , Brasil , Células Vero , Chlorocebus aethiops , Culex/virologia , Mosquitos Vetores/virologia , Filogenia , Arbovírus/isolamento & purificação , Arbovírus/genética , Arbovírus/classificação
7.
Molecules ; 29(17)2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39275117

RESUMO

This study proposes an affordable plasma device that utilizes a parallel-plate dielectric barrier discharge geometry with a metallic mesh electrode, featuring a straightforward 3D-printed design. Powered by a high-voltage supply adapted from a cosmetic plasma device, it operates on atmospheric air, eliminating the need for gas flux. Surface modification of polyethylene treated with this device was characterized and showed that the elemental composition after 15 min of plasma treatment decreased the amount of C to ~80 at% due to the insertion of O (~15 at%). Tested against Candida albicans and Staphylococcus aureus, the device achieved a reduction of over 99% in microbial load with exposure times ranging from 1 to 10 min. Simultaneously, the Vero cell viability remained consistently high, namely between 91% and 96% across exposure times. These results highlight this device's potential for the surface modification of materials and various infection-related applications, boasting affordability and facilitating effective antimicrobial interventions.


Assuntos
Candida albicans , Gases em Plasma , Staphylococcus aureus , Propriedades de Superfície , Candida albicans/efeitos dos fármacos , Gases em Plasma/química , Gases em Plasma/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Células Vero , Chlorocebus aethiops , Viabilidade Microbiana/efeitos dos fármacos , Polímeros/química
8.
Rev Bras Parasitol Vet ; 33(3): e001824, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39292065

RESUMO

Toxoplasma gondii is a coccidian protozoan of zoonotic importance that causes toxoplasmosis. Although the current treatments for toxoplasmosis may be associated with adverse effects and limited efficacy for different biological forms of the parasite, evidence suggests that alkaloid molecules such as harmaline and piperine exhibit antiparasitic effects against protozoa parasites. This investigation aimed to evaluate the in vitro effect of harmaline and piperine against T. gondii tachyzoites in infected Vero cell cultures. After 24 hours of host cell infection, the cultures were treated with harmaline or piperine (0.49 to 15.63 µg/mL). Negative and positive controls were RPMI/DMSO (0.1%) and sulfadiazine (200 µg/mL). Harmaline significantly reduced parasite multiplication by 20% compared to the negative control, while piperine decreased between 55.56% and 88.89% in a dose-dependent manner. According to an intracellular parasite proportion scale, it was observed that the Vero cells with low or moderate parasitic proliferation were more prevalent after the alkaloid treatment. The study demonstrated that the alkaloids had antiparasitic effects on T. gondii, with piperine being the most effective. Additional studies must be carried out to clarify other aspects of the action of the alkaloids on parasites.


Assuntos
Alcaloides , Benzodioxóis , Harmalina , Piperidinas , Alcamidas Poli-Insaturadas , Toxoplasma , Benzodioxóis/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/farmacologia , Toxoplasma/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Chlorocebus aethiops , Células Vero , Harmalina/farmacologia , Testes de Sensibilidade Parasitária
9.
Int J Biol Macromol ; 278(Pt 3): 134865, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39163951

RESUMO

The COVID-19 pandemic has revealed weaknesses in healthcare systems and underscored the need for advanced antimicrobial materials. This study investigates the quaternization of agar, a seaweed-derived polysaccharide, and the development of electrospun membranes for air filtration in facemasks and biomedical applications. Using the betacoronavirus MHV-3 as a model, quaternized agar and membranes achieved a 90-99.99 % reduction in viral load, without associated cytotoxicity. The quaternization process reduced the viscosity of the solution from 1.19 ± 0.005 to 0.64 ± 0.005 Pa.s and consequently the electrospun fiber diameter ranged from 360 to 185 nm. Membranes synthesized based on polyvinyl alcohol and thermally cross-linked with citric acid exhibited lower water permeability. Avoiding organic solvents in the electrospinning technique ensured eco-friendly production. This approach offers a promising way to develop biocompatible and functional materials for healthcare and environmental applications.


Assuntos
Ágar , SARS-CoV-2 , Ágar/química , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , COVID-19/prevenção & controle , Humanos , Inativação de Vírus/efeitos dos fármacos , Viscosidade , Membranas Artificiais , Animais , Álcool de Polivinil/química , Álcool de Polivinil/farmacologia , Pandemias/prevenção & controle , Chlorocebus aethiops , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia
10.
An Acad Bras Cienc ; 96(3): e20230309, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39166649

RESUMO

Brazil is renowned for its extensive plant biodiversity, with emphasis on Cymbopogon, C. citratus and C. nardus, with broad antimicrobial potential. Candidemias caused by Candida albicans are highly prevalent in immunosuppressed individuals and are associated with infections by biofilms on medical devices. The aim of this study was to evaluate the antimicrobial potential of essential oils C. citratus and C. nardus against C. albicans in planktonic and biofilm forms. Essential oils were obtained by hydrodistillation and chemical composition evaluated by GC-FID and GC-MS. The minimum inhibitory concentration was determined by the broth microdilution method and the synergy effect of essential oils and amphotericin B were evaluated by the checkerboard test. Biofilm activity was determined by the XTT assay. Cytotoxicity assays performed with VERO cells and molecular docking were performed to predict the effect of oil interaction on the SAP-5 enzyme site. The results showed activity of essential oils against planktonic cells and biofilm of C. albicans. Furthermore, the oils had a synergistic effect, and low cytotoxicity. Molecular docking showed interaction between Cadinene, Caryophyllen oxide, Germacrene D with SAP-5. The results indicate that Cymbopogon spp. studied are anti-Candida, with potential for further application in therapy against infections caused by C. albicans.


Assuntos
Antifúngicos , Biofilmes , Candida albicans , Cymbopogon , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Óleos Voláteis , Cymbopogon/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Antifúngicos/farmacologia , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Animais , Células Vero , Chlorocebus aethiops , Cromatografia Gasosa-Espectrometria de Massas
11.
Molecules ; 29(16)2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39202939

RESUMO

Marine organisms represent a potential source of secondary metabolites with various therapeutic properties. However, the pharmaceutical industry still needs to explore the algological resource. The species Caulerpa lamouroux Forssk presents confirmed biological activities associated with its major compound caulerpin, such as antinociceptive, spasmolytic, antiviral, antimicrobial, insecticidal, and cytotoxic. Considering that caulerpin is still limited, such as low solubility or chemical instability, it was subjected to a structural modifications test to establish which molecular regions could accept structural modification and to elucidate the cytotoxic bioactive structure in Vero cells (African green monkey kidney cells, Cercopithecus aethiops; ATCC, Manassas, VA, USA) and antiviral to Herpes simplex virus type 1. Substitution reactions in the N-indolic position with mono- and di-substituted alkyl, benzyl, allyl, propargyl, and ethyl acetate groups were performed, in addition to conversion to their acidic derivatives. The obtained analogs were submitted to cytotoxicity and antiviral activity screening against Herpes simplex virus type 1 by the tetrazolium microculture method. From the semi-synthesis, 14 analogs were obtained, and 12 are new. The cytotoxicity assay showed that caulerpin acid and N-ethyl-substituted acid presented cytotoxic concentrations referring to 50% of the maximum effect of 1035.0 µM and 1004.0 µM, respectively, values significantly higher than caulerpin. The antiviral screening of the analogs revealed that the N-substituted acids with methyl and ethyl groups inhibited Herpes simplex virus type 1-induced cytotoxicity by levels similar to the positive control acyclovir.


Assuntos
Antivirais , Herpesvirus Humano 1 , Antivirais/farmacologia , Antivirais/química , Chlorocebus aethiops , Herpesvirus Humano 1/efeitos dos fármacos , Células Vero , Animais , Relação Estrutura-Atividade , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos
12.
J Enzyme Inhib Med Chem ; 39(1): 2388207, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39140692

RESUMO

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.


Assuntos
Aldeído Liases , Antituberculosos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Antituberculosos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Relação Estrutura-Atividade , Aldeído Liases/antagonistas & inibidores , Aldeído Liases/metabolismo , Aldeído Liases/química , Células Vero , Estrutura Molecular , Cristalografia por Raios X , Chlorocebus aethiops , Animais , Guanina/farmacologia , Guanina/química , Guanina/análogos & derivados , Guanina/síntese química , Simulação de Acoplamento Molecular , Células Hep G2 , Modelos Moleculares
13.
Mar Drugs ; 22(8)2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39195485

RESUMO

Dengue, caused by the dengue virus (DENV), is a global health threat transmitted by Aedes mosquitoes, resulting in 400 million cases annually. The disease ranges from mild to severe, with potential progression to hemorrhagic dengue. Current research is focused on natural antivirals due to challenges in vector control. This study evaluates the antiviral potential of peptides derived from the microalgae Phaeodactylum tricornutum, known for its bioactive compounds. Microalgae were cultivated under controlled conditions, followed by protein extraction and hydrolysis to produce four peptide fractions. These fractions were assessed for cytotoxicity via the MTT assay and antiviral activity against DENV serotype 2 using flow cytometry and plaque formation assays. The 10-30 kDa peptide fraction, at 150 and 300 µg/mL concentrations, demonstrated no cytotoxicity and significantly reduced the percentage of infected cells and viral titers. These findings suggest that peptides derived from Phaeodactylum tricornutum exhibit promising antiviral activity against dengue virus serotype 2, potentially contributing to developing new therapeutic approaches for dengue.


Assuntos
Antivirais , Vírus da Dengue , Microalgas , Vírus da Dengue/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Animais , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/química , Dengue/tratamento farmacológico , Dengue/virologia , Peptídeos/farmacologia , Peptídeos/química , Sorogrupo , Chlorocebus aethiops , Humanos , Aedes/efeitos dos fármacos , Células Vero
14.
Curr Top Med Chem ; 24(25): 2224-2237, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39136505

RESUMO

OBJECTIVE: In this study, we have synthesized 19 Thiazolidine (TZD) derivatives to investigate their potential anti-ZIKV effects. METHODS: Nineteen thiazolidine derivatives were synthesized and evaluated for their cytotoxicity and antiviral activity against the ZIKA virus. RESULTS: Among them, six demonstrated remarkable selectivity against the ZIKV virus, exhibiting IC50 values of <5µM, and the other compounds did not demonstrate selectivity for the virus. Interestingly, several derivatives effectively suppressed the replication of ZIKV RNA copies, with derivatives significantly reducing ZIKV mRNA levels at 24 hours post-infection (hpi). Notably, two derivatives (ZKC-4 and -9) stood out by demonstrating a protective effect against ZIKV cell entry. Informed by computational analysis of binding affinity and intermolecular interactions within the NS5 domain's N-7 and O'2 positions, ZKC-4 and FT-39 displayed the highest predicted affinities. Intriguingly, ZKC-4 and ZKC-9 derivatives exhibited the most favorable predicted binding affinities for the ZIKV-E binding site. CONCLUSION: The significance of TZDs as potent antiviral agents is underscored by these findings, suggesting that exploring TZD derivatives holds promise for advancing antiviral therapeutic strategies.


Assuntos
Antivirais , Tiazolidinas , Zika virus , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Tiazolidinas/farmacologia , Tiazolidinas/química , Tiazolidinas/síntese química , Zika virus/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Replicação Viral/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Dose-Resposta a Droga , Animais , Chlorocebus aethiops , Células Vero , Simulação de Acoplamento Molecular
15.
Int J Mol Sci ; 25(14)2024 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-39063216

RESUMO

Although the disease caused by chikungunya virus (CHIKV) is of great interest to public health organizations around the world, there are still no authorized antivirals for its treatment. Previously, dihalogenated anti-CHIKV compounds derived from L-tyrosine (dH-Y) were identified as being effective against in vitro infection by this virus, so the objective of this study was to determine the mechanisms of its antiviral action. Six dH-Y compounds (C1 to C6) dihalogenated with bromine or chlorine and modified in their amino groups were evaluated by different in vitro antiviral strategies and in silico tools. When the cells were exposed before infection, all compounds decreased the expression of viral proteins; only C4, C5 and C6 inhibited the genome; and C1, C2 and C3 inhibited infectious viral particles (IVPs). Furthermore, C1 and C3 reduce adhesion, while C2 and C3 reduce internalization, which could be related to the in silico interaction with the fusion peptide of the E1 viral protein. Only C3, C4, C5 and C6 inhibited IVPs when the cells were exposed after infection, and their effect occurred in late stages after viral translation and replication, such as assembly, and not during budding. In summary, the structural changes of these compounds determine their mechanism of action. Additionally, C3 was the only compound that inhibited CHIKV infection at different stages of the replicative cycle, making it a compound of interest for conversion as a potential drug.


Assuntos
Antivirais , Febre de Chikungunya , Vírus Chikungunya , Tirosina , Replicação Viral , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/fisiologia , Tirosina/farmacologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Tirosina/química , Antivirais/farmacologia , Antivirais/química , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Animais , Replicação Viral/efeitos dos fármacos , Chlorocebus aethiops , Células Vero , Humanos , Internalização do Vírus/efeitos dos fármacos , Proteínas Virais/metabolismo
16.
Sci Rep ; 14(1): 15289, 2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961137

RESUMO

The limited availability of antivirals for new highly pathogenic strains of virus has become a serious public health. Therefore, news products against these pathogens has become an urgent necessity. Among the multiple sources for news antibiotics and antivirals, insect exudates or their products has become an increasingly frequent option. Insects emerged 350 million years ago and have showed a high adaptability and resistance to the most varied biomes. Their survival for so long, in such different environments, is an indication that they have a very efficient protection against environmental infections, despite not having a developed immune system like mammals. Since the ancient civilizations, the products obtained from the bee have been of great pharmacological importance, being used as antimicrobial, anti-inflammatory, antitumor and several other functions. Investigations of biological activity of propolis have been carried out, mainly in the species Apis mellifera, and its product have showed activity against some important viruses. However, for the Meliponini species, known as stingless bees, there are few studies, either on their chemical composition or on their biological activities. The importance of studying these bees is because they come from regions with native forests, and therefore with many species of plants not yet studied, in addition to which they are regions still free of pesticides, which guarantees a greater fidelity of the obtained data. Previous studies by our group with crude hydroalcoholic extract of propolis demonstrated an intense antiviral activity against Herpes, influenza, and rubella viruses. In this work, we chose to use aqueous extracts, which eliminates the presence of other compounds besides those originally present in propolis, in addition to extracting substances different from those obtained in alcoholic extracts. Therefore, this study aimed to identify, isolate and characterize compounds with antiviral effects from aqueous propolis extracts from Scaptotrigona aff postica, in emerging viruses such as zicavirus, chikungunya, and mayaro virus. The evaluation of the antiviral activity of the crude and purified material was performed by reducing infectious foci in VERO cell cultures. The results obtained with crude propolis, indicate a high reduction of zica virus (64×) and mayaro (128×) when was used 10% v/v of propolis. The reduction of chikungunya virus was of 256 fold, even when was used 5% v/v of propolis. The chemical characterization of the compounds present in the extracts was performed by high-pressure liquid chromatography. Through the purification of propolis by HPLC and mass spectrometry, it was possible to identify and isolate a peak with antiviral activity. This substance showed activity against all viruses tested. When purified fraction was used, the reduction observed was of 16 fold for zicavirus, 32 fold for mayaro virus and 512 fold for chikungunya virus. Likewise, it was observed that the antiviral response was concentration dependent, being more intense when propolis was added 2 h after the viral infection. Now we are carrying out the chemical characterization of the purified compounds that showed antiviral action.


Assuntos
Antivirais , Própole , Própole/farmacologia , Própole/química , Animais , Antivirais/farmacologia , Antivirais/química , Abelhas , Vírus Chikungunya/efeitos dos fármacos , Chlorocebus aethiops , Células Vero
17.
Protein Pept Lett ; 31(7): 532-543, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39039677

RESUMO

BACKGROUND: Peptide drugs are advantageous because they are subject to rational design and exhibit highly diverse structures and broad biological activities. The NS2B-NS3 protein is a particularly promising flavivirus therapeutic target, with extensive research on the development of inhibitors as therapeutic candidates, and was used as a model in this work to determine the mechanism by which GA-Hecate inhibits ZIKV replication. OBJECTIVE: The present study aimed to evaluate the potential of GA-Hecate, a new antiviral developed by our group, against the Brazilian Zika virus and to evaluate the mechanism of action of this compound on the flavivirus NS2B-NS3 protein. METHODS: Solid-phase peptide Synthesis, High-Performance Liquid Chromatography, and Mass Spectrometry were used to obtain, purify, and characterize the synthesized compound. Real-time and enzymatic assays were used to determine the antiviral potential of GA-Hecate against ZIKV. RESULTS: The RT-qPCR results showed that GA-Hecate decreased the number of ZIKV RNA copies in the virucidal, pre-treatment, and post-entry assays, with 5- to 6-fold fewer RNA copies at the higher nontoxic concentration in Vero cells (HNTC: 10 µM) than in the control cells. Enzymatic and kinetic assays indicated that GA-Hecate acts as a competitive ZIKV NS2B-NS3 protease inhibitor with an IC50 of 32 nM and has activity against the yellow fever virus protease. CONCLUSION: The results highlight the antiviral potential of the GA-Hecate bioconjugate and open the door for the development of new antivirals.


Assuntos
Antivirais , Proteínas não Estruturais Virais , Replicação Viral , Zika virus , Zika virus/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Chlorocebus aethiops , Células Vero , Replicação Viral/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Peptídeos/farmacologia , Peptídeos/química , RNA Helicases/metabolismo , RNA Helicases/antagonistas & inibidores , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/virologia , Humanos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Proteases Virais , Nucleosídeo-Trifosfatase , RNA Helicases DEAD-box
18.
Int J Pharm ; 660: 124304, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-38848799

RESUMO

Depression is one of the most common psychiatric disorders. Nanotechnology has emerged to optimize the pharmacological response. Therefore, the aim of this work was to develop and characterize liposomes and nanocapsules containing paroxetine hydrochloride and evaluate their antidepressant-like effect using the open field and tail suspension tests in mice. Liposomes and nanocapsules were prepared using the reverse-phase evaporation and nanoprecipitation methods, respectively. The particle size of the formulation ranged from 121.81 to 310.73 nm, the polydispersity index from 0.096 to 0.303, the zeta potential from -11.94 to -34.50 mV, the pH from 5.31 to 7.38, the drug content from 80.82 to 94.36 %, and the association efficiency was 98 %. Paroxetine hydrochloride showed slower release when associated with liposomes (43.82 %) compared to nanocapsules (95.59 %) after 10 h. In Vero cells, in vitro toxicity showed a concentration-dependent effect for paroxetine hydrochloride nanostructures. Both nanostructures decreased the immobility time in the TST at 2.5 mg/kg without affecting the number of crossings in the open field test, suggesting the antidepressant-like effect of paroxetine. In addition, the nanocapsules decreased the number of groomings, reinforcing the anxiolytic effect of this drug. These results suggest that the nanostructures were effective in preserving the antidepressant-like effect of paroxetine hydrochloride even at low doses.


Assuntos
Lipossomos , Nanocápsulas , Paroxetina , Animais , Paroxetina/administração & dosagem , Paroxetina/farmacologia , Paroxetina/química , Nanocápsulas/química , Camundongos , Chlorocebus aethiops , Masculino , Células Vero , Tamanho da Partícula , Liberação Controlada de Fármacos , Depressão/tratamento farmacológico , Elevação dos Membros Posteriores , Antidepressivos/administração & dosagem , Antidepressivos/química , Antidepressivos/farmacologia , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/química , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos
19.
Toxicol In Vitro ; 99: 105873, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38851601

RESUMO

Açaí (Euterpe oleracea MART) is a fruit of great importance for the Amazon region in nutritional, cultural and socioeconomic terms. In recent years, açaí has been the subject of several studies due to its beneficial properties for health, including effects against tumor cells. Therefore, the present work aimed to evaluate in vitro the genotoxic and cytotoxic effects of the clarified extract of açaí juice in a human metastatic gastric cancer cell line (AGP01 cells). For comparison purposes, a non-transformed cell line of African green monkey renal epithelial cells (VERO cells) was used. The viability assay by resazurin reduction, the comet assay, the determination of cell death by differential fluorescent dyes and the wound healing migration assay were performed. A reduction in viability was observed only in the AGP01 line within 72 h. There was no genotoxic damage or cell death (through apoptosis or necrosis) in any of the cell lines. However, açaí extract induced motility reduction in both cell lines. The reduction in cell viability and the induction of the anti-migratory effect in the AGP01 cell line opens perspectives for exploring the potential of açaí as an adjuvant in the treatment of gastric cancer.


Assuntos
Sobrevivência Celular , Dano ao DNA , Euterpe , Extratos Vegetais , Neoplasias Gástricas , Euterpe/química , Sobrevivência Celular/efeitos dos fármacos , Animais , Humanos , Neoplasias Gástricas/tratamento farmacológico , Extratos Vegetais/toxicidade , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Chlorocebus aethiops , Movimento Celular/efeitos dos fármacos , Ensaio Cometa , Células Vero
20.
Acta Trop ; 257: 107272, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38885823

RESUMO

The Orthoflavivirus ilheusense (ILHV) is an arbovirus that was first isolated in Brazil in 1944 during an epidemiologic investigation of yellow fever. Is a member of the Flaviviridae family and it belongs to the antigenic complex of the Ntaya virus group. Psorophora ferox is the primary vector of ILHV and this study presents the isolation and phylogenetic analysis of ILHV in a pool of Ps. ferox collected in the state of Goiás in 2021. Viral isolation tests were performed on Vero cells and C6/36 clones. The indirect immunofluorescence test (IFI) was used to confirm the positivity of the sample. The positive sample underwent RT-qPCR, sequencing, and phylogenetic analysis. This is the first report of ILHV circulation in this municipality and presented close relationship between this isolate and another ILHV isolate collected in the city of Belém (PA).


Assuntos
Culicidae , Filogenia , Animais , Brasil , Células Vero , Culicidae/virologia , Chlorocebus aethiops , Flavivirus/genética , Flavivirus/isolamento & purificação , Flavivirus/classificação , Mosquitos Vetores/virologia
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