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1.
Carbohydr Polym ; 332: 121884, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38431405

RESUMO

The global healthcare challenge posed by COVID-19 necessitates the continuous exploration for novel antiviral agents. Fucoidans have demonstrated antiviral activity. However, the underlying structure-activity mechanism responsible for the inhibitory activity of fucoidans from Ascophyllum nodosum (FUCA) and Undaria pinnatifida (FUCU) against SARS-CoV-2 remains unclear. FUCA was characterized as a homopolymer with a backbone structure of repeating (1 â†’ 3) and (1 â†’ 4) linked α-l-fucopyranose residues, whereas FUCU was a heteropolysaccharide composed of Fuc1-3Gal1-6 repeats. Furthermore, FUCA demonstrated significantly higher anti-SARS-CoV-2 activity than FUCU (EC50: 48.66 vs 69.52 µg/mL), suggesting the degree of branching rather than sulfate content affected the antiviral activity. Additionally, FUCA exhibited a dose-dependent inhibitory effect on ACE2, surpassing the inhibitory activity of FUCU. In vitro, both FUCA and FUCU treatments downregulated the expression of pro-inflammatory cytokines (IL-6, IFN-α, IFN-γ, and TNF-α) and anti-inflammatory cytokines (IL-10 and IFN-ß) induced by viral infection. In hamsters, FUCA demonstrated greater effectiveness in attenuating lung and gastrointestinal injury and reducing ACE2 expression, compared to FUCU. Analysis of the 16S rRNA gene sequencing revealed that only FUCU partially alleviated the gut microbiota dysbiosis caused by SARS-CoV-2. Consequently, our study provides a scientific basis for considering fucoidans as poteintial prophylactic food components against SARS-CoV-2.


Assuntos
Ascophyllum , COVID-19 , Polissacarídeos , Undaria , Humanos , Ascophyllum/química , Enzima de Conversão de Angiotensina 2 , SARS-CoV-2 , RNA Ribossômico 16S , Undaria/química , Citocinas , Inflamação , Antivirais/farmacologia , Antivirais/uso terapêutico
3.
J Med Virol ; 96(3): e29498, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38436148

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global threat to human health. In parallel with vaccines, efficacious antivirals are urgently needed. SARS-CoV-2 main protease (Mpro) is an attractive drug target for antiviral development owing to its key roles in virus replication and host immune evasion. Due to the limitations of currently available methods, the development of novel high-throughput screening assays is of the highest importance for the discovery of Mpro inhibitors. In this study, we first developed an improved fluorescence-based assay for rapid screening of Mpro inhibitors from an anti-infection compound library using a versatile dimerization-dependent red fluorescent protein (ddRFP) biosensor. Utilizing this assay, we identified MG-101 as a competitive Mpro inhibitor in vitro. Moreover, our results revealed that ensitrelvir is a potent Mpro inhibitor, but baicalein, chloroquine, ebselen, echinatin, and silibinin are not. Therefore, this robust ddRFP assay provides a faithful avenue for rapid screening and evaluation of Mpro inhibitors to fight against COVID-19.


Assuntos
COVID-19 , Proteases 3C de Coronavírus , Humanos , SARS-CoV-2 , Inibidores de Proteases/farmacologia , Antivirais/farmacologia
5.
J Clin Immunol ; 44(3): 80, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38462559

RESUMO

OBJECTIVE: We sought to explore the prevalence of type I interferon-neutralizing antibodies in a Chinese cohort and its clinical implications during the Omicron variant wave of SARS-CoV-2. METHODS: Type I interferon (IFN) autoantibodies possessing neutralizing capabilities were identified using luciferase assays. The capacity of the autoantibodies for in vitro interference with antiviral activity of IFN was assessed by using a SARS-CoV-2 replicon system. An analysis of the demographic and clinical profiles of patients exhibiting neutralizing antibodies was also conducted. RESULTS: In this cohort, 11.8% of severe/critical cases exhibited the existence of type I IFN-neutralizing antibodies, specifically targeting IFN-α2, IFN-ω, or both, with an elderly male patient tendency. Notably, these antibodies exerted a pronounced inhibitory effect on the antiviral activity of IFN against SARS-CoV-2 under controlled in vitro conditions. Furthermore, a noteworthy correlation was discerned between the presence of these neutralizing antibodies and critical clinical parameters, including C-reactive protein (CRP) levels, D-dimer levels, and lymphocyte counts. CONCLUSION: The presence of type I IFN-neutralizing antibodies is a pervasive risk factor for severe/critical COVID-19 in the Chinese population.


Assuntos
COVID-19 , Interferon Tipo I , Idoso , Humanos , Masculino , Autoanticorpos , COVID-19/epidemiologia , SARS-CoV-2 , Prevalência , China/epidemiologia , Anticorpos Neutralizantes , Antivirais
6.
Chem Biol Drug Des ; 103(3): e14500, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38467555

RESUMO

Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient-related factors while others are inclined to attribute this as a DAA side-effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell-cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in-house developed and validated LC-MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti-proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti-proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.


Assuntos
Carcinoma Hepatocelular , Hepatite C , Neoplasias Hepáticas , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Cromatografia Líquida , Espectrometria de Massas em Tandem , Proliferação de Células , Hepatite C/tratamento farmacológico , Hepacivirus , Proteína Quinase CDC2
7.
J Med Virol ; 96(3): e29516, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38469895

RESUMO

The serum chemokine C-X-C motif ligand-10 (CXCL10) and its unique receptor (CXCR3) may predict the prognosis of patients with chronic hepatitis B (CHB) treated with tenofovir disoproxil fumarate (TDF). Nevertheless, there are few reports on the profile of CXCL10 and CXCR3 and their clinical application in HBeAg (+) CHB patients during TDF antiviral therapy. CXCL10 and CXCR3 were determined in 118 CHB patients naively treated with TDF for at least 96 weeks at baseline and at treatment weeks 12 and 24. In addition, gene set enrichment analysis was used to examine the associated dataset from Gene Expression Omnibus and explore the gene sets associated with HBeAg seroconversion (SC). The change of CXCL10 (ΔCXCL10, baseline to 48-week TDF treatment) and CXCR3 (ΔCXCR3) is closely related to the possibility of HBeAg SC of CHB patients under TDF treatment. Immunohistochemical analysis of CXCL10/CXCR3 protein in liver tissue shows that there is a significant difference between paired liver biopsy samples taken before and after 96 weeks of successful TDF treatment of CHB patients (11 pairs) but no significance for unsuccessful TDF treatment (14 pairs). Multivariate Cox analysis suggests that the ΔCXCL10 is an independent predictive indicator of HBeAg SC, and the area under the receiver operating characteristic curve of the ΔCXCL10 in CHB patients is 0.8867 (p < 0.0001). Our results suggest that a lower descending CXCL10 level is associated with an increased probability of HBeAg SC of CHB patients during TDF therapy. Moreover, liver tissue CXCL10 might be involved in the immunological process of HBeAg SC.


Assuntos
Hepatite B Crônica , Humanos , Tenofovir , Antivirais , Antígenos E da Hepatite B , Soroconversão , Resultado do Tratamento , Vírus da Hepatite B/genética , DNA Viral , Quimiocina CXCL10
8.
Med Oncol ; 41(4): 85, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38472606

RESUMO

Human interferon-induced transmembrane protein family (IFITMs) consists of five main proteins. IFITM1, IFITM2, and IFITM3 can be induced by interferon, while IFITM5 and IFITM10 are insensitive to interferon. IFITMs has various functions, including well-researched antiviral effects. As a molecule whose expression is significantly increased by interferon in the immune microenvironment, IFITMs has drawn growing interest in recent years for their role in the cancer progression. Unlike antiviral effects, the role and mechanism of IFITMs in cancer progression have not been clearly studied, especially the role and molecular mechanism of IFITMs in pancreatic cancer are rarely reported in the literature. This article focuses on the role and potential mechanism of IFITMs in pancreatic cancer progression by analyzing the function and mechanism of IFITM1-3 in other cancers and conducting bioinformatics analysis using the databases, so as to provide a new target for pancreatic cancer therapy.


Assuntos
Interferons , Neoplasias Pancreáticas , Humanos , Interferons/metabolismo , Proteínas de Ligação a RNA/metabolismo , Antivirais , Microambiente Tumoral , Proteínas de Membrana/metabolismo
9.
J Med Virol ; 96(3): e29517, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38476091

RESUMO

Herbal medicines (HMs) are one of the main sources for the development of lead antiviral compounds. However, due to the complex composition of HMs, the screening of active compounds within these is inefficient and requires a significant time investment. We report a novel and efficient virus-based screening method for antiviral active compounds in HMs. This method involves the centrifugal ultrafiltration of viruses, known as the virus-based affinity ultrafiltration method (VAUM). This method is suitable to identify virus specific active compounds from complex matrices such as HMs. The effectiveness of the VAUM was evaluated using influenza A virus (IAV) H1N1. Using this method, four compounds that bind to the surface protein of H1N1 were identified from dried fruits of Terminalia chebula (TC). Through competitive inhibition assays, the influenza surface protein, neuraminidase (NA), was identified as the target protein of these four TC-derived compounds. Three compounds were identified by high performance liquid chromatography (HPLC) and liquid chromatography/mass spectrometry (LC/MS), and their anti-H1N1 activities were verified by examining the cytopathic effect (CPE) and by performing a virus yield reduction assay. Further mechanistic studies demonstrated that these three compounds directly bind to NA and inhibit its activity. In summary, we describe here a VAUM that we designed, one that can be used to accurately screen antiviral active compounds in HMs and also help improve the efficiency of screening antiviral drugs found in natural products.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Plantas Medicinais , Humanos , Ultrafiltração , Extratos Vegetais/farmacologia , Antivirais/farmacologia , Proteínas de Membrana
10.
BMC Cancer ; 24(1): 291, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438842

RESUMO

BACKGROUND: For chronic hepatitis B virus (HBV) infection patients, increasing evidence has demonstrated the effectiveness of expanding the indications and applicable population for antiviral therapy. However, the expanded indication of antiviral therapy for hepatocellular carcinoma (HCC) remains to be further explored. METHODS: 196 HBV-related HCC patients who received radical hepatectomy and nucleos(t)ide analogues (NAs) therapy at Sichuan Provincial People's Hospital were enrolled in this study. HCC recurrence, overall survival (OS), early virological (VR) and biochemical responses (BR) of patients were compared between different NAs therapy and the use of anti-programmed cell death protein 1 (PD-1) therapy. RESULTS: NAs therapy at different timing of surgery was a strong independent risk factor for postoperative recurrence and overall mortality of HBV-related HCC patients. Furthermore, in HCC patients who received postoperative anti-PD-1 therapy, patients with HBV DNA < 1000 copy/mL had significantly better recurrence-free survival (RFS) and OS than those with HBV DNA ≥ 1000 copy/mL (HR: 7.783; P = 0.002; HR: 6.699; P < 0.001). However, the differences of RFS and OS rates between entecavir group and tenofovir disoproxil fumarate group were not statistically significant. Similar results were also observed in the rates of early VR, BR and combined VR and BR. CONCLUSION: Timely and reasonable preoperative NAs therapy showed clinical benefit in improving the prognosis of patients with HBV-related HCC, even in the case of normal alanine aminotransferase (ALT) level and negative hepatitis e antigen (HBeAg). Furthermore, a possible synergistic effect between antiviral therapy and anti-PD-1 therapy was founded and need further verification.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Vírus da Hepatite B , DNA Viral , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Prognóstico , Antivirais/uso terapêutico
11.
Nat Commun ; 15(1): 2274, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38480702

RESUMO

One of the hopes for overcoming the antibiotic resistance crisis is the use of bacteriophages to combat bacterial infections, the so-called phage therapy. This therapeutic approach is generally believed to be safe for humans and animals as phages should infect only prokaryotic cells. Nevertheless, recent studies suggested that bacteriophages might be recognized by eukaryotic cells, inducing specific cellular responses. Here we show that in chickens infected with Salmonella enterica and treated with a phage cocktail, bacteriophages are initially recognized by animal cells as viruses, however, the cGAS-STING pathway (one of two major pathways of the innate antiviral response) is blocked at the stage of the IRF3 transcription factor phosphorylation. This inhibition is due to the inability of RNA polymerase III to recognize phage DNA and to produce dsRNA molecules which are necessary to stimulate a large protein complex indispensable for IRF3 phosphorylation, indicating the mechanism of the antiviral response impairment.


Assuntos
Bacteriófagos , Terapia por Fagos , Humanos , Animais , Bacteriófagos/fisiologia , Galinhas , Imunidade , Antivirais
12.
Sci Transl Med ; 16(738): eadi0979, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478629

RESUMO

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.


Assuntos
COVID-19 , Proteases 3C de Coronavírus , Humanos , SARS-CoV-2 , Mutação/genética , Antivirais/farmacologia , Antivirais/uso terapêutico , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico
13.
J Med Virol ; 96(3): e29512, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38483056

RESUMO

Coronaviruses (CoVs) have continuously posed a threat to human and animal health. However, existing antiviral drugs are still insufficient in overcoming the challenges caused by multiple strains of CoVs. And methods for developing multi-target drugs are limited in terms of exploring drug targets with similar functions or structures. In this study, four rounds of structural design and modification on salinomycin were performed for novel antiviral compounds. It was based on the strategy of similar topological structure binding properties of protein targets (STSBPT), resulting in the high-efficient synthesis of the optimal compound M1, which could bind to aminopeptidase N and 3C-like protease from hosts and viruses, respectively, and exhibit a broad-spectrum antiviral effect against severe acute respiratory syndrome CoV 2 pseudovirus, porcine epidemic diarrhea virus, transmissible gastroenteritis virus, feline infectious peritonitis virus and mouse hepatitis virus. Furthermore, the drug-binding domains of these proteins were found to be structurally similar based on the STSBPT strategy. The compounds screened and designed based on this region were expected to have broad-spectrum and strong antiviral activities. The STSBPT strategy is expected to be a fundamental tool in accelerating the discovery of multiple targets with similar effects and drugs.


Assuntos
Infecções por Coronavirus , Coronavirus , Animais , Gatos , Camundongos , Suínos , Humanos , Antivirais/química , Infecções por Coronavirus/tratamento farmacológico , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química
14.
BMC Infect Dis ; 24(1): 301, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468199

RESUMO

BACKGROUND: Globally, 80 million people are suffering from chronic Hepatitis C virus (HCV) infection. Sofosbuvir ribavirin-based anti-HCV therapy is associated with anemia and other adverse effects. Polymorphisms of Inosine triphosphatase (ITPA) gene may cause functional impairment in the Inosine triphosphate pyrophosphatase enzyme, resulting in enhanced sustained viral response (SVR) and protection from ribavirin-associated anemia in patients on therapy. The study objective was to investigate the effect of Inosine triphosphatase gene polymorphism on SVR achievement, hemoglobin decline and ribavirin dose reduction in patients on therapy. METHODS: This prospective cohort study was of 170 hepatitis C infected patients received 6-month sofosbuvir ribavirin therapy. Patient viral load, reduction in ribavirin amount, liver function test, and complete blood count were noted monthly. Inosine triphosphatase variants rs1127354 and rs7270101 were assessed through the restriction fragment length polymorphism and confirmed using Sanger sequencing. The impact of polymorphism on cumulative reduction of ribavirin, and anti-HCV therapy outcome were studied. RESULTS: A total of 74.3% of patients had ITPA rs1127354 CC genotype, 25.7% were CA and AA 0%. The frequency of ITPA genotype rs7270101-AA was 95%, AC 5%, and CC was 0%. ITPA rs1127354-CA had a notably positive impact on SVR achievement with a zero-relapse rate. ITPA rs1127354-CA genotype was significantly (P ˂0.05) protective against ≥ 2 g/dl Hb reduction from baseline to 1st, 2nd and 6th months of therapy. During treatment, Hb reduction ≥ 10 g/dl was frequently observed in rs1127354-CC genotype and rs7270101-AA genotype patients. Ribavirin dose reduction was significantly (P ˂0.05) high in rs1127354-CC genotype as compared to genotype CA whereas no significant difference was observed in ribavirin dose reduction in rs7270101 AA and non-AA genotype. Patient baseline characteristics such as age, body mass index, rs1127354-CC genotype, and baseline Hb were significantly associated with significant Hb reduction. CONCLUSION: Pretreatment evaluation of ITPA polymorphism can be a diagnostic tool to find out patients at risk of anemia and improve treatment adherence. ITPA genotype rs1127354-CA contributes to improved compliance with ribavirin dose and protects against hemoglobin decline in HCV patients while taking ribavirin-based therapy. However, ITPA rs1127354, rs7270101 polymorphism have no significant impact on SVR achievement.


Assuntos
Anemia , Hepatite C Crônica , Hepatite C , Humanos , Ribavirina/efeitos adversos , Sofosbuvir/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Antivirais/efeitos adversos , Hepacivirus/genética , Estudos Prospectivos , Polimorfismo de Nucleotídeo Único , Pirofosfatases/genética , Pirofosfatases/uso terapêutico , Anemia/induzido quimicamente , Anemia/genética , Hepatite C/tratamento farmacológico , Genótipo , Hemoglobinas/genética , Resultado do Tratamento
15.
Influenza Other Respir Viruses ; 18(3): e13264, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38468434

RESUMO

BACKGROUND: We aimed to describe a cohort of hematologic patients with COVID-19 treated with antivirals early. METHODS: Non-interventional chart review study. Comparison of baseline characteristics and outcomes in high-risk hematologic patients treated with remdesivir between December 2021 and April 2022 versus those treated with nirmatrelvir/ritonavir between May and August 2022. RESULTS: Eighty-three patients were analyzed. Forty-two received remdesivir, and 41 nirmatrelvir/ritonavir. Patients with remdesivir were younger, vaccinated with lower number of doses, and received prior corticosteroids less frequently and sotrovimab, hyperimmune plasma and corticosteroids more often. Viral shedding median (IQR) duration was 18 (13-23) and 11 (8-21) days in the remdesivir and nirmatrelvir/ritonavir groups, respectively (p = 0.004). Median (IQR) Ct values before treatment were similar in both groups. Within 5 days of treatment, median (IQR) Ct values were 26 (23-29) and 33 (30-37) in the remdesivir and nirmatrelvir/ritonavir groups, respectively (p < 0.0001). All patients were hospitalized for remdesivir administration and only four (9.8%) in the nirmatrelvir/ritonavir group. The overall outcomes in this cohort of COVID-19 patients with Omicron variant was good, as no patient needed oxygen or ICU admission. One patient in remdesivir group died from septic shock. No severe adverse event was recorded in both treatment groups. CONCLUSIONS: Patients with hematologic malignancies and non-severe COVID-19 who received nirmatrelvir/ritonavir experienced faster decrease in viral load and shorter viral shedding. Furthermore, besides the advantage of oral administration, nirmatrelvir/ritonavir administration reduced the need of hospital admission.


Assuntos
COVID-19 , Neoplasias Hematológicas , Lactamas , Leucina , Nitrilas , Prolina , Humanos , Ritonavir/uso terapêutico , SARS-CoV-2 , Corticosteroides , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19
16.
Sci Rep ; 14(1): 4629, 2024 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-38472312

RESUMO

Biosurfactants encompass structurally and chemically diverse molecules with surface active properties, and a broad industrial deployment, including pharmaceuticals. The interest is growing mainly for the low toxicity, biodegradability, and production from renewable sources. In this work, the optimized biosurfactant production by Pseudomonas aeruginosa BM02, isolated from the soil of a mining area in the Brazilian Amazon region was assessed, in addition to its antiviral, antitumor, and antimicrobial activities. The optimal conditions for biosurfactant production were determined using a factorial design, which showed the best yield (2.28 mg/mL) at 25 °C, pH 5, and 1% glycerol. The biosurfactant obtained was characterized as a mixture of rhamnolipids with virucidal properties against Herpes Simplex Virus, Coronavirus, and Respiratory Syncytial Virus, in addition to antimicrobial properties against Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecium), at 50 µg/mL. The antitumor activity of BS (12.5 µg/mL) was also demonstrated, with potential selectivity in reducing the proliferation of breast tumor cells, after 1 min of exposure. These results demonstrate the importance of studying the interconnection between cultivation conditions and properties of industrially important compounds, such as rhamnolipid-type biosurfactant from P. aeruginosa BM02, a promising and sustainable alternative in the development of new antiviral, antitumor, and antimicrobial prototypes.


Assuntos
Pseudomonas aeruginosa , Tensoativos , Tensoativos/química , Glicolipídeos/química , Antivirais
17.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474097

RESUMO

Since the appearance of SARS-CoV-2 in 2019, the ensuing COVID-19 (Corona Virus Disease 2019) pandemic has posed a significant threat to the global public health system, human health, life, and economic well-being. Researchers worldwide have devoted considerable efforts to curb its spread and development. The latest studies have identified five viral proteins, spike protein (Spike), viral main protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and viral helicase (Helicase), which play crucial roles in the invasion of SARS-CoV-2 into the human body and its lifecycle. The development of novel anti-SARS-CoV-2 drugs targeting these five viral proteins holds immense promise. Therefore, the development of efficient, high-throughput screening methodologies specifically designed for these viral proteins is of utmost importance. Currently, a plethora of screening techniques exists, with fluorescence-based assays emerging as predominant contenders. In this review, we elucidate the foundational principles and methodologies underpinning fluorescence-based screening approaches directed at these pivotal viral targets, hoping to guide researchers in the judicious selection and refinement of screening strategies, thereby facilitating the discovery and development of lead compounds for anti-SARS-CoV-2 pharmaceuticals.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Proteínas Virais , Antivirais/uso terapêutico , Peptídeo Hidrolases
18.
Molecules ; 29(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38474490

RESUMO

The Zika virus (ZIKV) is a mosquito-borne virus that already poses a danger to worldwide human health. Patients infected with ZIKV generally have mild symptoms like a low-grade fever and joint pain. However, severe symptoms can also occur, such as Guillain-Barré syndrome, neuropathy, and myelitis. Pregnant women infected with ZIKV may also cause microcephaly in newborns. To date, we still lack conventional antiviral drugs to treat ZIKV infections. Marine natural products have novel structures and diverse biological activities. They have been discovered to have antibacterial, antiviral, anticancer, and other therapeutic effects. Therefore, marine products are important resources for compounds for innovative medicines. In this study, we identified a marine natural product, harzianopyridone (HAR), that could inhibit ZIKV replication with EC50 values from 0.46 to 2.63 µM while not showing obvious cytotoxicity in multiple cellular models (CC50 > 45 µM). Further, it also reduced the expression of viral proteins and protected cells from viral infection. More importantly, we found that HAR directly bound to the ZIKV RNA-dependent RNA polymerase (RdRp) and suppressed its polymerase activity. Collectively, our findings provide HAR as an option for the development of anti-ZIKV drugs.


Assuntos
Produtos Biológicos , Piridonas , Infecção por Zika virus , Zika virus , Animais , Humanos , Feminino , Recém-Nascido , Gravidez , Antivirais/farmacologia , RNA Polimerase Dependente de RNA/metabolismo , Produtos Biológicos/farmacologia , Replicação Viral
19.
Molecules ; 29(5)2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38474509

RESUMO

We provide promising computational (in silico) data on phytochemicals (compounds 1-10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1-10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1-10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.


Assuntos
COVID-19 , Plantas Medicinais , Peptídeo Hidrolases , Simulação de Acoplamento Molecular , SARS-CoV-2 , Papaína , Simulação de Dinâmica Molecular , Compostos Fitoquímicos , Antivirais , Inibidores de Proteases
20.
J Int AIDS Soc ; 27(3): e26218, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38444112

RESUMO

INTRODUCTION: The HIV and hepatitis B virus (HBV) epidemics are interconnected with shared routes of transmission and specific antiviral drugs that are effective against both viruses. Nearly, 300 million people around the world live with chronic HBV, many of whom are from priority populations who could benefit from HIV prevention services. Oral pre-exposure prophylaxis (PrEP) for HIV has implications in the prevention and treatment of HBV infection, but many people at increased risk of HIV acquisition may instead prefer long-acting formulations of PrEP, which are currently not active against HBV. DISCUSSION: People at increased risk for HIV acquisition may also be at risk for or already be living with HBV infection. Oral PrEP with tenofovir is effective in preventing both HIV and HBV, and tenofovir is also the recommended treatment for chronic HBV infection. Although implementation of oral PrEP has been challenging in sub-Saharan Africa, investments in its scale-up could secondarily reduce the clinical impact of HBV. Long-acting PrEP, including injectable medicines and implantable rings, may overcome some of the implementation challenges associated with oral PrEP, such as daily pill burden, adherence challenges and stigma; however, current formulations of long-acting PrEP do not have activity against HBV replication. Ideally, PrEP programmes would offer both oral and long-acting formulations with HBV screening to optimize HIV prevention services and HBV prevention and care, when appropriate. People who are not immune to HBV would benefit from being vaccinated against HBV before initiating long-acting PrEP. People who remain non-immune to HBV despite vaccination may benefit from being offered oral, tenofovir-based PrEP given its potential for HBV PrEP. People using PrEP and living with HBV who are not linked to dedicated HBV care would also benefit from laboratory monitoring at PrEP sites to ensure safety when using and after stopping tenofovir. PrEP programmes are ideal venues to offer HBV screening, HBV vaccination for people who are non-immune and treatment with tenofovir-based PrEP for people with indications for HBV therapy. CONCLUSIONS: Long-acting PrEP holds promise for reducing HIV incidence, but its implications for the HBV epidemic, particularly in sub-Saharan Africa, should not be overlooked.


Assuntos
Infecções por HIV , Hepatite B , Profilaxia Pré-Exposição , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Tenofovir/uso terapêutico , Antivirais/uso terapêutico
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