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1.
Braz. j. biol ; 83: e248083, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1278546

RESUMO

Abstract Species of the genus Cordia have shown biological activities, such as anti-inflammatory, analgesic, antioxidant, antiviral, and antifungal activities. The species Cordia glabrata (MART) A.DC. Has no information concerning its phytochemical profile and possible biological activities. Thus, this study aimed to evaluate this profile in ethanolic extracts of young, adult and senescent leaves, as well as their antioxidant, photoprotective, antimicrobial, and virucidal potentials. Phytochemical analysis was performed by TLC (thin-layer chromatography) and showed the presence of flavonoids, tannins, and terpenes. The evaluation by UPLC-MS/MS (Ultra performance liquid chromatography - tandem mass spectrometer) evidenced the presence of caffeic (3.89 mgL-1), p-cumaric (6.13 mgL-1), and ferulic (0.58 mgL-1) acids, whilst, in GC/MS (Gas chromatography-mass spectrometry) analysis there was a greater amount of palmitic (51.17%), stearic (20.34%), linoleic (9.62%), and miristic (8.16%) fatty acids. The DPPH (2,2-Diphenyl-1-picrylhydrazyl) and ABTS+ (2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) radicals were used to verify the potential antioxidant activity, observing a better activity for the leaf extract in the adult phenological stage: 54.63 ± 1.06 µgmL-1 (DPPH) and 44.21 ± 1.69 mM (ABTS). The potential photoprotective activity of the extracts was determined by spectrophotometry and the in vitro values of SPF (Sun Protection Factor) in young and adult leaves (5.47 and 5.41, respectively) showed values close to the minimum SPF of 6.0 required by ANVISA (Brazilian Health Regulatory Agency). It was not observed an antimicrobial activity for Staphylococcus aureus with a minimum inhibitory concentration of 2000 μgmL-1, however the anti-herpetic assay against the Herpes simplex virus type 2 (HSV-2) showed a potent virucidal activity at the tested concentrations with CV50 value <0.195 μgmL-1 and a Selectivity Index (SI = CC50 / CV50) greater than 448. The results obtained in this study suggest that extracts of leaves of C. glabrata in their adult phenological stage have potential antioxidant, photoprotective and virucidal activity, considering in vitro test results.


Resumo Espécies do gênero Cordia apresentam atividades biológicas, como anti-inflamatória, analgésica, antioxidante, antiviral e antifúngica. Para a espécie Cordia glabrata (MART) A.DC., ainda não existem informações sobre seu perfil fitoquímico e possíveis atividades biológicas, deste modo, o presente estudo teve como objetivo avaliar este perfil em extratos etanólicos de folhas jovens, adultas e senescentes, bem como o potencial antioxidante, fotoprotetor, antimicrobiano e virucida. A análise fitoquímica foi realizada por CCD (Cromatografia em Camada Delgada), mostrando a presença de flavonóides, taninos e terpenos. Na avaliação por CLAE EM/EM (Cromatografia Líquida de Ultra Eficiência acoplada a Espectrometria de Massas) foi evidenciado a presença dos ácidos caféico (3,89 mgL-1), p-cumárico (6,13 mgL-1) e ferúlico (0,58 mgL-1), paralelamente, na CG/EM (Cromatografia Gasosa acoplada a Espectrometria de Massas) verificou-se maior quantidade dos ácidos graxos palmítico (51,17%), esteárico (20,34%), linoléico (9,62%) e mirístico (8,16%). Os radicais DPPH (2,2-Difenil-1-picrilhidrazil) e ABTS+ (2′-Azino-bis (ácido 3-etilbenzotiazolina-6-sulfônico)) foram utilizados para verificar o potencial antioxidante, observando-se uma atividade superior para o extrato da folha em sua fase fenológica adulta: 54,63 ± 1,06 µgmL-1 (DPPH) e 44,21 ± 1,69 mM (ABTS+). A potencial atividade fotoprotetora dos extratos foi determinada espectrofotometricamente e os valores in vitro de FPS (Fator de Proteção Solar) em folhas jovens e adultas (5,47 e 5,41 respectivamente) apresentaram valores próximos ao FPS mínimo de 6,0 exigido pela ANVISA (Agência Nacional de Vigilância Sanitária). Não foi observada atividade antimicrobiana para Staphylococcus aureus sendo a concentração inibitória mínima de 2000 μgmL-1, no entanto o ensaio anti-herpético contra o vírus Herpes simplex tipo 2 (HSV-2) mostrou uma potente atividade virucida nas concentrações testadas com um valor de CV50 <0,195 μgmL-1 e um Índice de Seletividade (IS = CC50 / CV50) maior que 448. Os resultados obtidos neste estudo sugerem que extratos de folhas de C. glabrata em seu estágio fenológico adulto apresentam potencial antioxidante, fotoprotetora e virucida, considerando os resultados de testes in vitro.


Assuntos
Cordia , Anti-Infecciosos , Antivirais/farmacologia , Brasil , Extratos Vegetais/farmacologia , Cromatografia Líquida , Folhas de Planta , Espectrometria de Massas em Tandem , Antioxidantes/farmacologia
2.
Biomater Adv ; 136: 212785, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35929318

RESUMO

Herpetic dermatitis and oral recurrent herpes (ORH) are among the most common human infections. Antiviral drugs such as acyclovir (ACV) are used in the standard treatment for ORH. Despite its therapeutic efficacy, ACV is continuously and repetitively administered in high doses. In this sense, the development of controlled release drug delivery systems such as core-shell fibers have a great potential in the treatment of ORH. In this work, poly(lactic acid)/poly(ethylene glycol) (PLA/PEG) fibers were produced by solution blow spinning (SBS) for the controlled release of ACV encapsulated in the core. PLA/PEG nanofibers containing four different blend ratios (100:0, 90:10, 80:20 and 70:30 wt%) without or with 10 wt% ACV were characterized by scanning electron microscopy (SEM), thermogravimetry (TG) and differential scanning calorimetry (DSC). The ACV release profile for 21 days was accessed by UV-Vis spectroscopy. Static water contact angles of the spun fiber mats were measured by the sessile drop method to evaluate fiber wettability upon contact with skin for transdermal release. Cytotoxicity and antiviral efficacy against Herpes simplex viruses (HSV-1) were evaluated using Vero cells. ACV addition did not impact on morphology, but slightly improved thermal stability of the fibers. Addition of hydrophilic PEG in PLA/PEG blends, however, increased drug release as confirmed by contact angle measurements and release profile. The in vitro tests showed the effectiveness of the drug delivery systems developed in reducing HSV-1 viral titer, which is related to the judicious combination of polymers used in the fibrous mats, in addition to not being cytotoxic to Vero cells. These results show the great potential of PLA/PEG solution blow-spun fibers in the controlled release of ACV to develop practical devices for the treatment of cold sores, while favoring the aesthetic appearance by covering them with a soft tissue patch (fibrous mats).


Assuntos
Nanofibras , Aciclovir/farmacologia , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Preparações de Ação Retardada/farmacologia , Humanos , Nanofibras/química , Poliésteres/química , Polietilenoglicóis/farmacologia , Células Vero
3.
PLoS One ; 17(8): e0270273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35925919

RESUMO

Chronic hepatitis B virus (HBV) infection is characterized by the presence of high circulating levels of non-infectious lipoprotein-like HBV surface antigen (HBsAg) particles thought to contribute to chronic immune dysfunction in patients. Lipid and metabolomic analysis of humanized livers from immunodeficient chimeric mice (uPA/SCID) revealed that HBV infection dysregulates several lipid metabolic pathways. Small molecule inhibitors of lipid biosynthetic pathway enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase, and subtilisin kexin isozyme-1/site-1 protease in HBV-infected HepG2-NTCP cells demonstrated potent and selective reduction of extracellular HBsAg. However, a liver-targeted ACC inhibitor did not show antiviral activity in HBV-infected liver chimeric mice, despite evidence of on-target engagement. Our study suggests that while HBsAg production may be dependent on hepatic de novo lipogenesis in vitro, this may be overcome by extrahepatic sources (such as lipolysis or diet) in vivo. Thus, a combination of agents targeting more than one lipid metabolic pathway may be necessary to reduce HBsAg levels in patients with chronic HBV infection.


Assuntos
Hepatite B Crônica , Hepatite B , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , DNA Viral/metabolismo , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Lipídeos/uso terapêutico , Camundongos , Camundongos SCID
4.
Sci Rep ; 12(1): 13337, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35922447

RESUMO

Researchers are focused on discovering compounds that can interfere with the COVID-19 life cycle. One of the important non-structural proteins is endoribonuclease since it is responsible for processing viral RNA to evade detection of the host defense system. This work investigates a hierarchical structure-based virtual screening approach targeting NSP15. Different filtering approaches to predict the interactions of the compounds have been included in this study. Using a deep learning technique, we screened 823,821 compounds from five different databases (ZINC15, NCI, Drug Bank, Maybridge, and NCI Diversity set III). Subsequently, two docking protocols (extra precision and induced fit) were used to assess the binding affinity of the compounds, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy. Interestingly, one compound (ZINC000104379474) from the ZINC15 database has been found to have a good binding affinity of - 7.68 kcal/Mol. The VERO-E6 cell line was used to investigate its therapeutic effect in vitro. Half-maximal cytotoxic concentration and Inhibitory concentration 50 were determined to be 0.9 mg/ml and 0.01 mg/ml, respectively; therefore, the selectivity index is 90. In conclusion, ZINC000104379474 was shown to be a good hit for targeting the virus that needs further investigations in vivo to be a drug candidate.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Endorribonucleases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas não Estruturais Virais/genética
5.
Front Public Health ; 10: 911551, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35923969

RESUMO

Background: Increased interferon (IFN)-gamma inducible protein-10 (IP-10) level has been shown to be associated with sustained virologic responses (SVRs) to pegylated interferon-alpha 2a/ribavirin-based therapy in patients with chronic hepatitis C (CHC). We investigated the relationship between IP-10 and treatment response in patients with CHC treated with direct-acting antiviral agents (DAAs) therapy. Methods: We measured the dynamic changes of IP-10 in samples from 90 patients with CHC. The serum IP-10 levels, intrahepatic expressions of IP-10 mRNA, and protein were determined, respectively. For the in vitro experiments, the expression changes of IP-10 in hepatitis C virus (HCV)-replicating Huh-7 cells with or without non-structural protein 5A (NS5A) inhibitor were analyzed using real-time reverse transcription-polymerase chain reaction and Western blotting. Results: Patients with chronic hepatitis C had increased baseline IP-10 levels, intrahepatic IP-10 mRNA, and protein expression. After initiating DAAs therapy, serum IP-10 levels decreased gradually in patients who achieved cure, whereas in patients who failed the therapy, IP-10 levels did not change significantly or recovered from the initial decline. Multivariate logistic regression analysis confirmed that baseline IP-10 level ≤ 450 pg/ml and decline >30% at 12 weeks independently predicted the SVR in patients with CHC who received DAAs. In vitro, the expression of IP-10 mRNA and protein in HCV-replicating Huh-7 cells increased significantly. However, such activities were downregulated by NS5A inhibitor, followed by the reduction of HCV RNA levels and a decline in IP-10 levels. Conclusion: IP-10 interfered with HCV replication in hepatocytes and the dynamic decline in IP-10 levels during DAA treatment predicted the SVR in patients with CHC.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais/farmacologia , Antivirais/uso terapêutico , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/uso terapêutico , Quimioterapia Combinada , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C Crônica/tratamento farmacológico , Humanos , RNA Mensageiro/uso terapêutico
6.
Cell Death Dis ; 13(8): 684, 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35933402

RESUMO

Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFNs (IFN-λ) exhibit cell-type specific and long-lasting functions in auto-inflammation, tumorigenesis, and antiviral defense. Here, we identify the deubiquitinating enzyme USP22 as central regulator of basal IFN-λ secretion and SARS-CoV-2 infections in human intestinal epithelial cells (hIECs). USP22-deficient hIECs strongly upregulate genes involved in IFN signaling and viral defense, including numerous IFN-stimulated genes (ISGs), with increased secretion of IFN-λ and enhanced STAT1 signaling, even in the absence of exogenous IFNs or viral infection. Interestingly, USP22 controls basal and 2'3'-cGAMP-induced STING activation and loss of STING reversed STAT activation and ISG and IFN-λ expression. Intriguingly, USP22-deficient hIECs are protected against SARS-CoV-2 infection, viral replication, and the formation of de novo infectious particles, in a STING-dependent manner. These findings reveal USP22 as central host regulator of STING and type III IFN signaling, with important implications for SARS-CoV-2 infection and antiviral defense.


Assuntos
COVID-19 , Interferon Tipo I , Proteínas de Membrana/metabolismo , Ubiquitina Tiolesterase , Antivirais/farmacologia , Humanos , Interferon Tipo I/genética , Interferons/metabolismo , Pandemias , SARS-CoV-2 , Ubiquitina Tiolesterase/metabolismo
7.
Life Sci Alliance ; 5(12)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35926873

RESUMO

Human milk is important for antimicrobial defense in infants and has well demonstrated antiviral activity. We evaluated the protective ability of human milk against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a human fetal intestinal cell culture model. We found that, in this model, human milk blocks SARS-CoV-2 replication, irrespective of the presence of SARS-CoV-2 spike-specific antibodies. Complete inhibition of both enveloped Middle East respiratory syndrome coronavirus and human respiratory syncytial virus infections was also observed, whereas no inhibition of non-enveloped enterovirus A71 infection was seen. Transcriptome analysis after 24 h of the intestinal monolayers treated with human milk showed large transcriptomic changes from human milk treatment, and subsequent analysis suggested that ATP1A1 down-regulation by milk might be of importance. Inhibition of ATP1A1 blocked SARS-CoV-2 infection in our intestinal model, whereas no effect on EV-A71 infection was seen. Our data indicate that human milk has potent antiviral activity against particular (enveloped) viruses by potentially blocking the ATP1A1-mediated endocytic process.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Antivirais/farmacologia , Humanos , Leite Humano
8.
Drug Des Devel Ther ; 16: 2463-2478, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35941927

RESUMO

The current pandemic caused by the COVID-19 disease has reached everywhere in the world and has affected every aspect of our lives. As of the current data, the World Health Organization (WHO) has reported more than 300 million confirmed COVID-19 cases worldwide and more than 5 million deaths. Mpro is an enzyme that plays a key role in the life cycle of the SARS-CoV-2 virus, and it is vital for the disease progression. The Mpro enzyme seems to have several allosteric sites that can hinder the enzyme catalytic activity. Furthermore, some of these allosteric sites are located at or nearby the dimerization interface which is essential for the overall Mpro activity. In this review paper, we investigate the potential of the Mpro allosteric site to act as a drug target, especially since they interestingly appear to be resistant to mutation. The work is illustrated through three subsequent sections: First, the two main categories of Mpro allosteric sites have been explained and discussed. Second, a total of six pockets have been studied and evaluated for their druggability and cavity characteristics. Third, the experimental and computational attempts for the discovery of new allosteric inhibitors have been illustrated and discussed. To sum up, this review paper gives a detailed insight into the feasibility of developing new Mpro inhibitors to act as a potential treatment for the COVID-19 disease.


Assuntos
COVID-19 , SARS-CoV-2 , Sítio Alostérico , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/metabolismo
9.
Phytother Res ; 36(8): 3232-3247, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35943221

RESUMO

The current COVID-19 pandemic caused by SARS-Cov-2 is responsible for more than 6 million deaths globally. The development of broad-spectrum and cost-effective antivirals is urgently needed. Medicinal plants are renowned as a complementary approach in which antiviral natural products have been established as safe and effective drugs. Here, we report that the percolation extract of Spatholobus suberectus Dunn (SSP) is a broad-spectrum viral entry inhibitor against SARS-CoV-1/2 and other enveloped viruses. The viral inhibitory activities of the SSP were evaluated by using pseudotyped SARS-CoV-1 and 2, HIV-1ADA and HXB2 , and H5N1. SSP effectively inhibited viral entry and with EC50 values ranging from 3.6 to 5.1 µg/ml. Pre-treatment of pseudovirus or target cells with SSP showed consistent inhibitory activities with the respective EC50 value of 2.3 or 2.1 µg/ml. SSP blocked both SARS-CoV-2 spike glycoprotein and the host ACE2 receptor. In vivo studies indicated that there was no abnormal toxicity and behavior in long-term SSP treatment. Based on these findings, we concluded that SSP has the potential to be developed as a drug candidate for preventing and treating COVID-19 and other emerging enveloped viruses.


Assuntos
COVID-19 , Virus da Influenza A Subtipo H5N1 , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Humanos , Pandemias/prevenção & controle , SARS-CoV-2
10.
Theranostics ; 12(12): 5317-5329, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910807

RESUMO

Human pluripotent stem cell derived brain organoids offer an unprecedented opportunity for various applications as in vitro model. Currently, human brain organoids as models have been used to understand virus-induced neurotoxicity. Methods: The brain organoids were separately challenged by multiple viruses including influenza viruses (H1N1-WSN and H3N2-HKT68), Enteroviruses (EV68 and EV71) and Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) to investigate the impaired effect of these viruses on human brain development. Results: The brain organoids challenged by influenza viruses had decreased overall organoid size, while enteroviruses infected brain organoids displayed the opposite result. Then, we found WSN preferentially infected MAP2+ neurons compared to SOX2+ neural stem cells (NSCs) and GFAP+ astrocytes in brain organoids, and induced apoptosis of NSCs and neurons, and released inflammatory factors (TNF-α, INF-γ, and IL-6), facilitating brain damage. Furthermore, transcriptional profiling revealed several co-upregulated genes (CSAG3 and OAS2) and co-downregulated genes (CDC20B, KCNJ13, OTX2-AS1) after WSN infection for 24 hpi and 96 hpi, implicating target for antiviral drugs development. Finally, we explored compound PYC-12 could significantly suppress virus infection, apoptosis, and inflammatory responses. Conclusions: Collectively, we established a tractable experimental model to investigate the impact and mechanism of virus infection on human brain development.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Antivirais/farmacologia , Encéfalo , Humanos , Vírus da Influenza A Subtipo H3N2 , Organoides
11.
Front Immunol ; 13: 951984, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911774

RESUMO

Senecavirus A (SVA), also known as Seneca Valley virus, is a recently discovered picornavirus that can cause swine vesicular disease, posing a great threat to the global swine industry. It can replicate efficiently in cells, but the molecular mechanism remains poorly understood. This study determined the host's differentially expressed proteins (DEPs) during SVA infection using dimethyl labeling based on quantitative proteomics. Among the DE proteins, DDX21, a member of the DEAD (Asp-Glu-Ala-Asp)-box RNA helicase (DDX) family, was downregulated and demonstrated inhibiting SVA replication by overexpression and knockdown experiment. To antagonize this antiviral effect of DDX21, SVA infection induces the degradation of DDX21 by 2B and 3C proteins. The Co-IP results showed that 2B and 3C did not interact with DDX21, suggesting that the degradation of DDX21 did not depend on their interaction. Moreover, the 3C protein protease activity was necessary for the degradation of DDX21. Furthermore, our study revealed that the degradation of DDX21 by 2B and 3C proteins of SVA was achieved through the caspase pathway. These findings suggest that DDX21 was an effective antiviral factor for suppressing SVA infection and that SVA antagonized its antiviral effect by degrading DDX21, which will be useful to guide further studies into the mechanism of mutual regulation between SVA and the host.


Assuntos
Antivirais , Picornaviridae , Animais , Antivirais/farmacologia , Caspases , Picornaviridae/genética , Suínos , Proteínas Virais/metabolismo
13.
Curr Microbiol ; 79(9): 284, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35947206

RESUMO

Exploration of secondary metabolites secreted by new Actinobacteria taxa isolated from unexplored areas, can increase the possibility to obtain new compounds which can be developed into new drugs for the treatment of serious diseases such as hepatitis C. In this context, one actinobacterial strain, CG3, has been selected based on the results of polyphasic characterization, which indicate that it represents a new putative species within the genus Nocardiopsis. Two fractions (F2 and F3), prepared from the culture of strain CG3 in soybean medium, exhibited a pronounced antiviral activity against the HCV strain Luc-Jc1. LC-HRESIMS analysis showed different bioactive compounds in both active fractions (F2 and F3), including five polyenic macrolactams (kenalactams A-E), three isoflavone metabolites, along with mitomycin C and one p-phenyl derivative. Furthermore, feeding with 1% of methionine, lysine or alanine as a unique nitrogen source, induced the production of three novel kenalactam derivatives.


Assuntos
Actinobacteria , Nocardiopsis , Actinobacteria/genética , Antivirais/farmacologia , DNA Bacteriano/metabolismo , Filogenia , RNA Ribossômico 16S/metabolismo , Análise de Sequência de DNA , Microbiologia do Solo
14.
J Enzyme Inhib Med Chem ; 37(1): 2158-2168, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35943189

RESUMO

Zinc pyrithione (1a), together with its analogues 1b-h and ruthenium pyrithione complex 2a, were synthesised and evaluated for the stability in biologically relevant media and anti-SARS-CoV-2 activity. Zinc pyrithione revealed potent in vitro inhibition of cathepsin L (IC50=1.88 ± 0.49 µM) and PLPro (IC50=0.50 ± 0.07 µM), enzymes involved in SARS-CoV-2 entry and replication, respectively, as well as antiviral entry and replication properties in an ex vivo system derived from primary human lung tissue. Zinc complexes 1b-h expressed comparable in vitro inhibition. On the contrary, ruthenium complex 2a and the ligand pyrithione a itself expressed poor inhibition in mentioned assays, indicating the importance of the selection of metal core and structure of metal complex for antiviral activity. Safe, effective, and preferably oral at-home therapeutics for COVID-19 are needed and as such zinc pyrithione, which is also commercially available, could be considered as a potential therapeutic agent against SARS-CoV-2.


Assuntos
COVID-19 , Rutênio , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Catepsina L , Humanos , Compostos Organometálicos , Piridinas , SARS-CoV-2
15.
FASEB J ; 36(8): e22409, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35792897

RESUMO

Interferon regulatory factor 7 (IRF7), as the interferon-stimulated gene, maximally drives type I interferon (IFN) production. However, the mechanisms by which the biological function of IRF7 is regulated remain elusive. In this study, we found that IRF7 selectively interacted with the neuralized E3 ubiquitin-protein ligase 3 (NEURL3). In concomitant with IRF7 induction, NEURL3 is upregulated by NF-κB signaling in the late phase of viral infection. Moreover, NEURL3 augmented the host antiviral immune response through ubiquitinating IRF7. A mechanistic study revealed that NEURL3 triggered K63-linked poly-ubiquitination on IRF7 lysine 375, which in turn epigenetically enhanced the transcription of interferon-stimulated genes (ISGs) through disruption of the association of IRF7 with Histone Deacetylase 1 (HDAC1), consequently augmenting host antiviral immune response. Accordingly, Neurl3-/- mice produced less type I IFNs and exhibited increased susceptibility to viral infection. Taken together, our findings identify NEURL3 as an E3 ubiquitin ligase of IRF7 and shed new light on the positive regulation of IRF7 in host antiviral immune signaling.


Assuntos
Interferon Tipo I , Ubiquitina-Proteína Ligases/metabolismo , Viroses , Animais , Antivirais/farmacologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/metabolismo , Interferon Tipo I/genética , Camundongos , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
16.
Cell Mol Biol (Noisy-le-grand) ; 67(5): 387-398, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35818229

RESUMO

Despite the accelerated emerging of vaccines, development against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) drugs discovery is still in demand. Repurposing the existing drugs is an ideal time/cost-effective strategy to tackle the clinical impact of SARS CoV-2. Thereby, the present study is a promising strategy that proposes the repurposing of approved drugs against pivotal proteins that are responsible for the viral propagation of SARS-CoV-2 virus Angiotensin-converting enzyme-2 (ACE2; 2AJF), 3CL-protease: main protease (6LU7), Papain-like protease (6W9C), Receptor Binding Domain of Spike protein (6VW1), Transmembrane protease serine 2 (TMPRSS-2; 5AFW) and Furin (5MIM) by in silico methods. Molecular docking results were analyzed based on the binding energy and active site interactions accomplished with pharmacokinetic analysis. It was observed that both anisomycin and oleandomycin bind to all selected target proteins with good binding energy, achieving the most favorable interactions. Considering the results of binding affinity, pharmacokinetics and toxicity of anisomycin and oleandomycin, it is proposed that they can act as potential drugs against the SARS CoV-2 infection. Further clinical testing of the reported drugs is essential for their use in the treatment of SARS CoV-2 infection.


Assuntos
COVID-19 , SARS-CoV-2 , Anisomicina , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Humanos , Simulação de Acoplamento Molecular , Oleandomicina
17.
Cell Mol Biol (Noisy-le-grand) ; 67(5): 371-386, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35818230

RESUMO

Due to the emergency and uncontrolled situation caused by the COVID-19 pandemic that arising in the entire world, it is necessary to choose available drugs that can inhibit or prevent the disease. Therefore, the repurposing of the commercial antibiotic, dirithromycin has been screened for the first time against fifteen receptors and compared to the azithromycin using a molecular docking approach to identify possible SARS-CoV-2 inhibitors. Our docking results showed that dirithromycin fit significantly in the Furin catalytic pocket having the lowest binding score (-9.9 Kcal/mol) with respect to azithromycin (-9.4 Kcal/mol) and can interact and block both Asp154 and Ser368 residues by Van der Walls interaction as well as bound to His194 and Ser368 residues via hydrogen bonds. Good results were also obtained with the Tmprss-2 receptor. A Molecular Dynamic simulation was assessed to confirm this interaction. Additionally, detailed receptor-ligand interactions with SARS-CoV-2 and pro-inflammatory mediators were investigated suggesting more target information with interesting results. The findings of this study are very efficient and provide a basis for the development of dirithromycin for clinical trial applications to be efficient in treating SARS-CoV-2 infections.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Azitromicina/química , Azitromicina/farmacologia , Azitromicina/uso terapêutico , COVID-19/tratamento farmacológico , Eritromicina/análogos & derivados , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
18.
Cell Mol Biol (Noisy-le-grand) ; 67(4): 143-162, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35809292

RESUMO

Developing new prophylactic and therapeutic agents with broad-spectrum antiviral activities is urgently needed to combat emerging human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since no available clinically antiviral drugs have been approved to eradicate COVID-19 as of the writing of this report, this study aimed to investigate bioactive short peptides from Allium subhirsutum L. (Hairy garlic) extracts identified through HR-LC/MS analysis that could potentially hinder the multiplication cycle of SARS-CoV-2 via molecular docking study. The obtained promising results showed that the peptides (Asn-Asn-Asn) possess the highest binding affinities of -8.4 kcal/mol against S protein, (His-Phe-Gln) of -9.8 kcal/mol and (Gln-His-Phe) of -9.7 kcal/mol towards hACE2, (Thr-Leu-Trp) of -10.3 kcal/mol and (Gln-Phe-Tyr) of -9.8 kcal/mol against furin. Additionally, the identified peptides show strong interactions with the targeted and pro-inflammatory ranging from -8.1 to -10.5 kcal/mol for NF-κB-inducing kinase (NIK), from -8.2 to -10 kcal/mol for phospholipase A2 (PLA2), from -8.0 to -10.7 kcal/mol for interleukin-1 receptor-associated kinase 4 (IRAK-4), and from -8.6 to -11.6 kcal/mol for the cyclooxygenase 2 (COX2) with Gln-Phe-Tyr model seems to be the most prominent. Results from pharmacophore, drug-likeness and ADMET prediction analyses clearly evidenced the usability of the peptides to be developed as an effective drug, beneficial for COVID-19 treatment.


Assuntos
Allium , COVID-19 , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2
19.
Front Cell Infect Microbiol ; 12: 856711, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774410

RESUMO

Porcine epidemic diarrhea virus (PEDV) could cause lethal diarrhea and dehydration in suckling piglets, which can adversely affect the development of the global swine industry. The lack of effective therapeutical and prophylactic treatment especially for PEDV variant strains underlines the importance of effective antiviral strategies, such as identification of novel antiviral agents. In the present study, the antiviral activity of cinchonine against PEDV was investigated in Vero CCL81 and LLC-PK1 cells at a non-cytotoxic concentration determined by Cell Counting Kit-8 assay in vitro. We found that cinchonine exhibited a significant suppression effect against PEDV infection and its inhibitory action was primarily focused on the early stage of PEDV replication. Moreover, we also observed that cinchonine could significantly induce autophagy by detecting the conversion of LC3-I to LC3-II by using western blot analysis. Cinchonine treatment could inhibit PEDV replication in a dose-dependent manner in Vero CCL81 cells, while this phenomenon disappeared when autophagy was attenuated by pre-treatment with autophagy inhibitor 3MA. Consequently, this study indicated that cinchonine can inhibit PEDV replication via inducing cellular autophagy and thus from the basis for successful antiviral strategies which potentially suggest the possibility of exploiting cinchonine as a novel antiviral agent.


Assuntos
Infecções por Coronavirus , Vírus da Diarreia Epidêmica Suína , Doenças dos Suínos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Autofagia , Chlorocebus aethiops , Alcaloides de Cinchona , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Vírus da Diarreia Epidêmica Suína/fisiologia , Suínos , Doenças dos Suínos/tratamento farmacológico , Células Vero , Replicação Viral
20.
Arch Microbiol ; 204(8): 522, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879582

RESUMO

Herpes simplex virus-1 (HSV-1) is an important human neurotropic virus infecting 70% of the world population. Due to the emergence of viral resistance via mutations in HSV-1 genes and some of the adverse effects of antiviral compounds, there is a growing need for safe, novel, and effective therapeutic and preventive strategies. The aim of the present study was to investigate for the first time the potential antiviral activity of Shouchella clausii probiotic strain and bacterial supernatant against HSV-1. The MTT assay was used to determine the possible cytotoxicity of the S. clausii and bacterial supernatant. Vero cells were treated by S. clausii, bacterial supernatant, and HSV-1 under pre-treatment (incubation of Vero cells with S. clausii then HSV-1 inoculation), pre-incubation (mixture of co-incubated HSV-1/S. clausii added to Vero cell), competition (adding HSV-1 and S. clausii into Vero cells simultaneously) and post-treatment (Vero cells inoculated with HSV-1 then incubated with S. clausii) assays. Viral titer reduction (TCID50) and viral DNA relative quantification by real-time PCR were measured in each experimental condition. The results indicated that S. clausii and its supernatant had the greatest inhibitory activity toward HSV-1 in pre-treatment assay. The HSV-1 titer treated with S. clausii, and bacterial supernatant was 3.6 and 2.2 Log10TCID50/mL lower compared to the control (7.66 Log10TCID50/mL). Results showed an antiviral effect of S. clausii and its supernatant. S. clausii could be considered as a novel inhibitor for HSV-1 infection.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Probióticos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Chlorocebus aethiops , Herpes Simples/tratamento farmacológico , Humanos , Células Vero
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