Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2.
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ABSTRACT:
SUBMITTER: Kandeil A
PROVIDER: S-EPMC8232731 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a virus that causes the infectious disease coronavirus disease-2019. Currently, there is no effective drug for the prevention and treatment of this virus. This study aimed to identify secondary metabolites that potentially inhibit the key proteins of SARS-CoV-2. This was an in silico molecular docking study of several secondary metabolites of Indonesian herbal plant compounds and other metabolites with antiviral testing history. Virtual screening using AutoDock Vina of 216 Lipinski rule-compliant plant metabolites was performed on 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), and spike glycoprotein. Ligand preparation was performed using JChem and Schrödinger's software, and virtual protein elucidation was performed using AutoDockTools version 1.5.6. Virtual screening identified several RdRp, spike, and 3CLpro inhibitors. Justicidin D had binding affinities of -8.7, -8.1, and -7.6 kcal mol-1 on RdRp, 3CLpro, and spike, respectively. 10-methoxycamptothecin had binding affinities of -8.5 and -8.2 kcal mol-1 on RdRp and spike, respectively. Inoxanthone had binding affinities of -8.3 and -8.1 kcal mol-1 on RdRp and spike, respectively, while binding affinities of caribine were -9.0 and -7.5 mol-1 on 3CLpro and spike, respectively. Secondary metabolites of compounds from several plants were identified as potential agents for SARS-CoV-2 therapy.
| S-EPMC8177144 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV), a newly identified group 2 coronavirus, is the causative agent of severe acute respiratory syndrome, a life-threatening form of pneumonia in humans. Coronavirus replication and transcription are highly specialized processes of cytoplasmic RNA synthesis that localize to virus-induced membrane structures and were recently proposed to involve a complex enzymatic machinery that, besides RNA-dependent RNA polymerase, helicase, and protease activities, also involves a series of RNA-processing enzymes that are not found in most other RNA virus families. Here, we characterized the enzymatic activities of a recombinant form of the SARS-CoV helicase (nonstructural protein [nsp] 13), a superfamily 1 helicase with an N-terminal zinc-binding domain. We report that nsp13 has both RNA and DNA duplex-unwinding activities. SARS-CoV nsp13 unwinds its substrates in a 5'-to-3' direction and features a remarkable processivity, allowing efficient strand separation of extended regions of double-stranded RNA and DNA. Characterization of the nsp13-associated (deoxy)nucleoside triphosphatase ([dNTPase) activities revealed that all natural nucleotides and deoxynucleotides are substrates of nsp13, with ATP, dATP, and GTP being hydrolyzed slightly more efficiently than other nucleotides. Furthermore, we established an RNA 5'-triphosphatase activity for the SARS-CoV nsp13 helicase which may be involved in the formation of the 5' cap structure of viral RNAs. The data suggest that the (d)NTPase and RNA 5'-triphosphatase activities of nsp13 have a common active site. Finally, we established that, in SARS-CoV-infected Vero E6 cells, nsp13 localizes to membranes that appear to be derived from the endoplasmic reticulum and are the likely site of SARS-CoV RNA synthesis.
| S-EPMC415832 | biostudies-literature
Project description:The ongoing pandemic of coronavirus disease 2019 (COVID-19) posed a major challenge to the public health. Currently, no proven antiviral treatment for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is available. Here we report compounds pentalysine β-carbonylphthalocyanine zinc (ZnPc5K) and chlorin e6 (ce6) potently inhibited the viral infection and replication in vitro with EC50 values at nanomolar level. These compounds were first identified by screening a panel of photosensitizers for photodynamic viral inactivation. Such viral inactivation strategy is implementable, and has unique advantages, including resistance to virus mutations, affordability compared to the monoclonal antibodies, and lack of long-term toxicity.
| S-EPMC8216852 | biostudies-literature
Project description:We previously found that N-89 and its derivative, N-251, which are being developed as antimalarial compounds, showed multiple antiviral activities including hepatitis C virus (HCV). In this study, we focused on the most characterized anti-HCV activity of N-89(N-251) to clarify their antiviral mechanisms. We first prepared cells exhibiting resistance to N-89(N-251) than the parental cells by serial treatment of HCV-RNA-replicating parental cells with N-89(N-251). Then, we newly generated HCV-RNA-replicating cells with the replacement of HCV-RNAs derived from N-89(N-251)-resistant cells and parental cells. Using these cells, we examined the degree of inhibition of HCV-RNA replication by N-89(N-251) and found that the host and viral factors contributed almost equally to the resistance to N-89(N-251). To further examine the contribution of the host factors, we selected several candidate genes by cDNA microarray analysis and found that the upregulated expression of at least RAC2 and CKMT1B genes independently and differently contributed to the acquisition of an N-89(N-251)-resistant phenotype. For the viral factors, we selected several mutation candidates by the genetic comparative analysis of HCV-RNAs and showed that at least one M414I mutation in the HCV NS5B contributed to the resistance to N-89. Moreover, we demonstrated that the combination of host factors (RAC2 and/or CKMT1B) and a viral factor (M414I mutation) additively increased the resistance to N-89. In summary, we identified the host and viral factors contributing to the acquisition of N-89(N-251)-resistance in HCV-RNA replication. These findings will be useful for clarification of the antiviral mechanism of N-89(N-251).
| S-EPMC8103717 | biostudies-literature
Project description:Viral infections are one of the main cause of diseases worldwide due to the rising trends of migration, urbanization and global mobility of humans. The outbreak of corona virus diseases caused by SARS-CoV (year 2003), MERS-CoV (year 2012) and SARS-CoV-2 (year 2019) raised global health concerns. The side effects associated with the conventional drugs and increase in cases of anti-microbial resistance have led the researchers to switch to natural sources, especially plants, as they have immense potential to be used as antiviral agents. The aim of the article is to summarize the evidences of the bioactive phytocompounds from different plants as an effective alternative for the treatment of infections caused by coronaviruses. However, the use of most plant compounds succumbs to limitations due to lack of experimental evidences and safety studies. Therefore, further research and studies are required to validate their therapeutic uses for wide application of plant-based medicine, including anti-virals.
| S-EPMC7826042 | biostudies-literature
Project description:BackgroundGenetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began to emerge in 2020 and have been spreading globally during the coronavirus disease 2019 (COVID-19) pandemic. Despite the presence of different COVID-19 vaccines, the discovery of effective antiviral therapeutics for the treatment of patients infected with SARS-CoV-2 are still urgently needed. A natural amino acid, 5-aminolevulinic acid (5-ALA), has exhibited both antiviral and anti-inflammatory activities. In a previous study, we demonstrated an in vitro antiviral effect of 5-ALA against SARS-CoV-2 infection without significant cytotoxicity. In the present study, we sought to investigate whether 5-ALA with or without sodium ferrous citrate (SFC) can inhibit in vitro both the original SARS-CoV-2 Wuhan strain and its variants, including the Alpha, Beta, Gamma and Delta strains.MethodsThe antiviral activity of ALA with or without SFC was determined in Vero-E6 cell. The virus inhibition was quantified by real time RT-PCR.ResultsCo-administration of 5-ALA and SFC inhibited the Wuhan, Alpha and Delta variants of SARS-CoV-2 with IC50 values of 235, 173 and 397 µM, respectively, and the Beta and Gamma variants with IC50 values of 1311 and 1516 µM.ConclusionOur study suggests that 5-ALA with SFC warrants accelerated clinical evaluation as an antiviral drug candidate for treating patients infected with SARS-CoV-2 variants.
| S-EPMC8739347 | biostudies-literature
Project description:Influenza virus and coronavirus, belonging to enveloped RNA viruses, are major causes of human respiratory diseases. The aim of this study was to investigate the broad spectrum antiviral activity of a naturally existing sulfated polysaccharide, lambda-carrageenan (λ-CGN), purified from marine red algae. Cell culture-based assays revealed that the macromolecule efficiently inhibited both influenza A and B viruses with EC50 values ranging from 0.3 to 1.4 μg/ml, as well as currently circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an EC50 value of 0.9 ± 1.1 μg/ml. No toxicity to the host cells was observed at concentrations up to 300 μg/ml. Plaque titration and western blot analysis verified that λ-CGN reduced expression of viral proteins in cell lysates and suppressed progeny virus production in culture supernatants in a dose-dependent manner. This polyanionic compound exerts antiviral activity by targeting viral attachment to cell surface receptors and preventing virus entry. Moreover, its intranasal administration to mice during influenza A viral challenge not only alleviated infection-mediated reductions in body weight but also protected 60% of mice from virus-induced mortality. Thus, λ-CGN could be a promising antiviral agent for preventing infection with several respiratory viruses.
| S-EPMC7804421 | biostudies-literature
Project description:A coronavirus disease 2019 (COVID-19) disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created significant concern since December 2019 worldwide. The virus is known to be highly transmissible. Heterogenic clinical features even vary more among SARS-CoV-2 variants from asymptomatic forms to severe symptoms. Previous studies revealed an association between COVID-19 and vitamin D deficiency resulting from its low levels in COVID-19 patients. To our knowledge, there is no scientific investigation that evaluates the direct association between SARS-CoV-2 variants of concern and vitamin D receptor ( VDR ) gene markers in Cyprus. Thus, the present study aimed to identify the putative impact of VDR gene polymorphisms on SARS-CoV-2 infection among different variants. The nasopharyngeal swabs were taken from a total number of 600 patients who were admitted to Near East University Hospital COVID-19 Polymerase Chain Reaction (PCR) Diagnosis Laboratory for routine SARS-CoV-2 real-time quantitative reverse transcription PCR (RT-qPCR) test. The RT-qPCR negative resulting samples were taken as control samples ( n = 300). On the contrary, the case group consisted of patients who were SARS-CoV-2 RT-qPCR positive, infected with either SARS-CoV-2 Alpha ( n = 100), Delta ( n = 100), or Omicron ( n = 100) variants. Two VDR gene polymorphisms, Taq I-rs731236 T > C and Fok I-rs10735810 C > T, were genotyped by polymerase chain reaction-restriction fragment length polymorphism. The mean age of the COVID-19 patient's ± standard deviation was 46.12 ± 12.36 and 45.25 ± 12.71 years old for the control group ( p > 0.05). The gender distribution of the patient group was 48.3% female and 51.7% male and for the control group 43% female and 57% male ( p > 0.05). Significant differences were observed in genotype frequencies of FokI and TaqI variants between SARS-CoV-2 patients compared to the control group ( p < 0.005). Furthermore, the risk alleles, FokI T allele and TaqI C, were found to be statistically significant (odds ratio [OR] = 1.80, 95% confidence interval [CI] = 1.42-2.29, OR = 1.62, 95% CI = 1.27-2.05, respectively) in COVID-19 patients. The highest number of patients with wild-type genotype was found in the control group, which is 52.9% compared with 17.5% in the case group. Moreover, most of the COVID-19 patients had heterozygous/homozygous genotypes, reaching 82.5%, while 47.1% of the control group patients had heterozygous/homozygous genotypes. Our results suggested that patients with FokI and TaqI polymorphisms might tend to be more susceptible to getting infected with SARS-CoV-2. Overall, findings from this study provided evidence regarding vitamin D supplements recommendation in individuals with vitamin D deficiency/insufficiency in the peri- or post-COVID-19 pandemic.
| S-EPMC9935054 | biostudies-literature
Project description:In addition to members causing milder human infections, the Coronaviridae family includes potentially lethal zoonotic agents causing severe acute respiratory syndrome (SARS) and the recently emerged Middle East respiratory syndrome. The ∼30-kb positive-stranded RNA genome of coronaviruses encodes a replication/transcription machinery that is unusually complex and composed of 16 nonstructural proteins (nsps). SARS-CoV nsp12, the canonical RNA-dependent RNA polymerase (RdRp), exhibits poorly processive RNA synthesis in vitro, at odds with the efficient replication of a very large RNA genome in vivo. Here, we report that SARS-CoV nsp7 and nsp8 activate and confer processivity to the RNA-synthesizing activity of nsp12. Using biochemical assays and reverse genetics, the importance of conserved nsp7 and nsp8 residues was probed. Whereas several nsp7 mutations affected virus replication to a limited extent, the replacement of two nsp8 residues (P183 and R190) essential for interaction with nsp12 and a third (K58) critical for the interaction of the polymerase complex with RNA were all lethal to the virus. Without a loss of processivity, the nsp7/nsp8/nsp12 complex can associate with nsp14, a bifunctional enzyme bearing 3'-5' exoribonuclease and RNA cap N7-guanine methyltransferase activities involved in replication fidelity and 5'-RNA capping, respectively. The identification of this tripartite polymerase complex that in turn associates with the nsp14 proofreading enzyme sheds light on how coronaviruses assemble an RNA-synthesizing machinery to replicate the largest known RNA genomes. This protein complex is a fascinating example of the functional integration of RNA polymerase, capping, and proofreading activities.
| S-EPMC4169972 | biostudies-literature
Project description:(1) Background: Drug repositioning is an unconventional drug discovery approach to explore new therapeutic benefits of existing drugs. Currently, it emerges as a rapid avenue to alleviate the COVID-19 pandemic disease. (2) Methods: Herein, we tested the antiviral activity of anti-microbial and anti-inflammatory Food and Drug Administration (FDA)-approved drugs, commonly prescribed to relieve respiratory symptoms, against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the viral causative agent of the COVID-19 pandemic. (3) Results: Of these FDA-approved antimicrobial drugs, Azithromycin, Niclosamide, and Nitazoxanide showed a promising ability to hinder the replication of a SARS-CoV-2 isolate, with IC50 of 0.32, 0.16, and 1.29 µM, respectively. We provided evidence that several antihistamine and anti-inflammatory drugs could partially reduce SARS-CoV-2 replication in vitro. Furthermore, this study showed that Azithromycin can selectively impair SARS-CoV-2 replication, but not the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). A virtual screening study illustrated that Azithromycin, Niclosamide, and Nitazoxanide bind to the main protease of SARS-CoV-2 (Protein data bank (PDB) ID: 6lu7) in binding mode similar to the reported co-crystalized ligand. Also, Niclosamide displayed hydrogen bond (HB) interaction with the key peptide moiety GLN: 493A of the spike glycoprotein active site. (4) Conclusions: The results suggest that Piroxicam should be prescribed in combination with Azithromycin for COVID-19 patients.
| S-EPMC7761982 | biostudies-literature