scholarly journals Broad-spectrum antivirals of protoporphyrins inhibit the entry of highly pathogenic emerging viruses

2020 ◽  
Author(s):  
Shengsheng Lu ◽  
Xiaoyan Pan ◽  
Daiwei Chen ◽  
Xi Xie ◽  
Yan Wu ◽  
...  
Keyword(s):  
Puerto Rico ◽  
Broad Spectrum ◽  
Influenza A ◽  
Rational Design ◽  
Host Cells ◽  
Mechanistic Study ◽  
Control Group ◽  
Enveloped Viruses ◽  
Essential Components ◽  
Antiviral Activities

AbstractSevere emerging and re-emerging viral infections such as Lassa fever, Avian influenza (AI), and COVID-19 caused by SARS-CoV-2 urgently call for new strategies for the development of broad-spectrum antivirals targeting conserved components in the virus life cycle. Viral lipids are essential components, and viral-cell membrane fusion is the required entry step for most unrelated enveloped viruses. In this paper, we identified a porphyrin derivative of protoporphyrin IX (PPIX) that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses including Lassa virus (LASV), Machupo virus (MACV), and SARS-CoV-2 as well as various subtypes of influenza A viral strains with IC50 values ranging from 0.91±0.25 μM to 1.88±0.34 μM. A mechanistic study using influenza A/Puerto Rico/8/34 (H1N1) as a testing strain showed that PPIX inhibits the infection in the early stage of virus entry through biophysically interacting with the hydrophobic lipids of enveloped virions, thereby inhibiting the formation of the negative curvature required for fusion and blocking the entry of enveloped viruses into host cells. In addition, the preliminary antiviral activities of PPIX were further assessed by testing mice infected with the influenza A/Puerto Rico/8/34 (H1N1) virus. The results showed that compared with the control group without drug treatment, the survival rate and mean survival time of the mice treated with PPIX were apparently prolonged. These data encourage us to conduct further investigations using PPIX as a lead compound for the rational design of lipid-targeting antivirals for the treatment of infection with enveloped viruses.

scholarly journals Molecular Docking of Broad-Spectrum Antibodies on Hemagglutinins of Influenza A Virus

2019 ◽  
Vol 15 ◽  
pp. 117693431987693
Author(s):  
Khanh PB Le ◽  
Phuc-Chau Do ◽  
Rommie E Amaro ◽  
Ly Le
Keyword(s):  
Influenza A Virus ◽  
Broad Spectrum ◽  
Influenza A ◽  
Rational Design ◽  
Interaction Analysis ◽  
Virus Antigen ◽  
Influenza Viruses ◽  
Antigen Binding ◽  
Universal Vaccine ◽  
In Silico Studies

Influenza A has caused several deadly pandemics throughout human history. The virus is often resistant to developed treatments because of its genetic drift or shift property. Broad-spectrum antibodies show a promising potential to overcome the resistance of influenza viruses. In silico studies on broad-reactive antibodies and their interactions with hemagglutinins might shed light on the rational design of a universal vaccine. In this study, 11 broad-spectrum antibodies (or antigen-binding fragments) and 14 hemagglutinins of H3N2 and H5N1 strains were docked and analyzed to provide information about the construction of the scaffold for using universal antibodies against the influenza A virus. Antigen-binding fragments that have high number of appearances in the top 3 within each H3 and H5 subtypes were chosen for protein-protein interaction analysis. The results show that while the hydrogen bond is important for Ab/Fab binding to H3, the H5-Ab/Fab system may need cation-pi interaction for a strong interaction.

scholarly journals The Influenza A Virus Genotype Determines the Antiviral Function of NF-κB

2016 ◽  
Vol 90 (17) ◽  
pp. 7980-7990 ◽  
Author(s):  
Sharmistha Dam ◽  
Michael Kracht ◽  
Stephan Pleschka ◽  
M. Lienhard Schmitz
Keyword(s):  
Transcription Factor ◽  
Influenza A Virus ◽  
Influenza A ◽  
Genome Engineering ◽  
Reverse Genetics ◽  
Host Cells ◽  
Avian Host ◽  
Essential Components ◽  
Antiviral Function

ABSTRACTThe role of NF-κB in influenza A virus (IAV) infection does not reveal a coherent picture, as pro- and also antiviral functions of this transcription factor have been described. To address this issue, we used clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9)-mediated genome engineering to generate murine MLE-15 cells lacking two essential components of the NF-κB pathway. Cells devoid of either the central NF-κB essential modulator (NEMO) scaffold protein and thus defective in IκB kinase (IKK) activation or cells not expressing the NF-κB DNA-binding and transactivation subunit p65 were tested for propagation of the SC35 virus, which has an avian host range, and its mouse-adapted variant, SC35M. While NF-κB was not relevant for replication of SC35M, the absence of NF-κB activity increased replication of the nonadapted SC35 virus. This antiviral effect of NF-κB was most prominent upon infection of cells with low virus titers as they usually occur during the initiation phase of IAV infection. The defect in NF-κB signaling resulted in diminished IAV-triggered phosphorylation of interferon regulatory factor 3 (IRF3) and expression of the antiviral beta interferon (IFN-β) gene. To identify the viral proteins responsible for NF-κB dependency, reassortant viruses were generated by reverse genetics. SC35 viruses containing the SC35M segment encoding neuraminidase (NA) were completely inert to the inhibitory effect of NF-κB, emphasizing the importance of the viral genotype for susceptibility to the antiviral functions of NF-κB.IMPORTANCEThis study addresses two different issues. First, we investigated the role of the host cell transcription factor NF-κB in IAV replication by genetic manipulation of IAVs by reverse genetics combined with targeted genome engineering of host cells using CRISPR-Cas9. The analysis of these two highly defined genetic systems indicated that the IAV genotype can influence whether NF-κB displays an antiviral function and thus might in part explain incoherent results from the literature. Second, we found that perturbation of NF-κB function greatly improved the growth of a nonadapted IAV, suggesting that NF-κB may contribute to the maintenance of the host species barrier.

scholarly journals Broad-Spectrum Antiviral Natural Products from the Marine-Derived Penicillium sp. IMB17-046

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2821 ◽  
Author(s):  
Jiao Li ◽  
Yujia Wang ◽  
Xiaomeng Hao ◽  
Shasha Li ◽  
Jia Jia ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
2D Nmr ◽  
Antibacterial Activities ◽  
Gastric Diseases ◽  
X Ray Crystallography ◽  
Penicillium Sp ◽  
Ic50 Values ◽  
Antiviral Activities ◽  
New Compounds

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3β-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 μM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1–16 μg/mL.

scholarly journals Respiratory and systemic humoral and cellular immune responses of pigs to a heterosubtypic influenza A virus infection

2001 ◽  
Vol 82 (11) ◽  
pp. 2697-2707 ◽  
Author(s):  
Paul P. Heinen ◽  
Els A. de Boer-Luijtze ◽  
Andre T. J. Bianchi
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Virus Infection ◽  
Broad Spectrum ◽  
Influenza A ◽  
Virus Transmission ◽  
Influenza Virus Infection ◽  
H3n2 Virus ◽  
Control Group ◽  
Immune Control

The level of heterosubtypic immunity (Het-I) and the immune mechanisms stimulated by a heterosubtypic influenza virus infection were investigated in pigs. Pigs are natural hosts for influenza virus and, like humans, they host both subtypes H1N1 and H3N2. Marked Het-I was observed when pigs were infected with H1N1 and subsequently challenged with H3N2. After challenge with H3N2, pigs infected earlier with H1N1 did not develop fever and showed reduced virus excretion compared with non-immune control pigs. In addition, virus transmission to unchallenged group-mates could be shown by virus isolation in the non-immune control group but not in the group infected previously with H1N1. Pigs infected previously with homologous H3N2 virus were protected completely. After challenge with H3N2, pigs infected previously with H1N1 showed a considerable increase in serum IgG titre to the conserved extracellular domain of M2 but not to the conserved nucleoprotein. These results suggest that antibodies against external conserved epitopes can have an important role in broad-spectrum immunity. After primary infection with both H1N1 and H3N2, a long-lived increase was observed in the percentage of CD8+ T cells in the lungs and in the lymphoproliferation response in the blood. Upon challenge with H3N2, pigs infected previously with H1N1 again showed an increase in the percentage of CD8+ T cells in the lungs, whereas pigs infected previously with H3N2 did not, suggesting that CD8+ T cells also have a role in Het-I. To confer broad-spectrum immunity, future vaccines should induce antibodies and CD8+ T cells against conserved antigens.

scholarly journals Vaccination of pigs with a DNA construct expressing an influenza virus M2–nucleoprotein fusion protein exacerbates disease after challenge with influenza A virus

2002 ◽  
Vol 83 (8) ◽  
pp. 1851-1859 ◽  
Author(s):  
Paul P. Heinen ◽  
Frans A. Rijsewijk ◽  
Els A. de Boer-Luijtze ◽  
André T. J. Bianchi
Keyword(s):  
Influenza Virus ◽  
Fusion Protein ◽  
Influenza A Virus ◽  
Broad Spectrum ◽  
Influenza A ◽  
Core Protein ◽  
Swine Influenza Virus ◽  
Clinical Signs ◽  
Swine Influenza ◽  
Control Group

In mice, vaccines inducing antibodies to the extracellular domain of the M2 protein (M2e) can confer protection to influenza A virus infection. Unlike the surface glycoproteins, haemagglutinin and neuraminidase, this domain of M2 is highly conserved and is therefore a potential broad-spectrum immunogen. In this study, the protection conferred by vaccines inducing antibodies to M2e was evaluated in a challenge model for swine influenza in pigs. A protein resulting from the fusion between M2e and the hepatitis B virus core protein (M2eHBc), with or without adjuvant, was evaluated. In addition, a DNA construct expressing a fusion protein between M2e and influenza virus nucleoprotein (M2eNP) was evaluated to see if the broad-spectrum protection conferred by antibodies could be further enhanced by T helper cells and cytotoxic T cells. All vaccines induced an antibody response against M2e, and the M2eNP DNA vaccine additionally induced an influenza virus-specific lymphoproliferation response. However, after challenge with a swine influenza virus (H1N1), no protection was observed in the vaccinated groups compared with the non-vaccinated control group. On the contrary, vaccinated pigs showed more severe clinical signs than the control pigs. The M2eNP DNA-vaccinated pigs showed the most severe clinical signs and three out of six pigs died on days 1 and 2 post-challenge. These results indicate that antibodies to M2e, especially in combination with cell-mediated immune responses, exacerbate disease. Thus, clinical signs after infection should be observed closely in further studies using M2e as an immunogen and caution should be exercised in using M2e in humans.

scholarly journals Multiple gene targeting siRNAs for down regulation of Immediate Early-2 (Ie2) and DNA polymerase genes mediated inhibition of novel rat Cytomegalovirus (strain All-03)

2020 ◽  
Author(s):  
Krishnan Nair Balakrishnan ◽  
Ashwaq Ahmed Abdullah ◽  
Jamilu Abubakar Bala ◽  
Faez Firdaus Abdullah Jesse ◽  
Che Azurahanim Che Abdullah ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Colorimetric Assay ◽  
Opportunistic Pathogen ◽  
Digital Pcr ◽  
Host Cells ◽  
Effective Vaccine ◽  
Control Group ◽  
Polymerase Gene ◽  
Antiviral Activities ◽  
Dna Polymerase Gene

Abstract Background Cytomegalovirus (CMV) is an opportunistic pathogen that causes severe complications in congenitally infected newborns and non-immunocompetent individuals. Developing an effective vaccine is a major public health priority and current drugs are fronting resistance and side effects on recipients. In the present study, with the aim of exploring new strategies to counteract CMV replication, several anti-CMV siRNAs targeting IE2 and DNA polymerase gene regions were characterized and used as in combinations for antiviral therapy. Methods The rat embryo fibroblast (REF) cells were transfected with multi siRNA before infecting with CMV strain ALL-03. Viral growth inhibition was measured by TCID50, cytopathic effect (CPE) and droplet digital PCR (ddPCR) while IE2 and DNA polymerase gene knockdown was determined by real-time PCR. Ganciclovir was deployed as a control to benchmark the efficacy of antiviral activities of respective individual siRNAs. Results There was no cytotoxicity encountered for all the combinations of siRNAs on REF cells analyzed by MTT colorimetric assay (P > 0.05). Cytopathic effects (CPE) in cells infected by RCMV ALL-03 developed significantly less and at much slower rate compared to control group. The expression of targeted genes was downregulated successfully resulted in significant reduction (P < 0.05) of viral mRNA and DNA copies (dpb + dpc: 79%, 68%; dpb + ie2b: 68%, 60%; dpb + dpc + ie2b: 48%, 42%). Flow cytometry analysis showed a greater percentage of viable and early apoptosis of combined siRNAs-treated cells compared to control group. Notably, the siRNAs targeting gene regions were sequenced and no any mutation was identified, thereby avoiding the formation of mutant with potential resistant viruses. Conclusions In conclusion. The study demonstrated a tremendous promise of innovative approach with the deployment of combined siRNAs targeting at several genes simultaneously with the aim to control CMV replication in host cells.

Discovery of Some Antiviral Natural products to fight against Novel Corona Virus (SARS-CoV-2) using Insilico approach

2020 ◽  
Vol 23 ◽  
Author(s):  
Ashish Shah ◽  
Vaishali Patel ◽  
Bhumika Parmar
Keyword(s):  
Binding Affinity ◽  
Protein S ◽  
Docking Studies ◽  
Spike Protein ◽  
Enveloped Viruses ◽  
Bioactivity Prediction ◽  
Corona Virus ◽  
Main Protease ◽  
Antiviral Activities ◽  
Deadly Disease

Background: Novel Corona virus is a type of enveloped viruses with a single stranded RNA enclosing helical nucleocapsid. The envelope consists of spikes on the surface which are made up of proteins through which virus enters into human cells. Until now there is no specific drug or vaccine available to treat COVID-19 infection. In this scenario, reposting of drug or active molecules may provide rapid solution to fight against this deadly disease. Objective: We had selected 30 phytoconstituents from the different plants which are reported for antiviral activities against corona virus (CoVs) and performed insilico screening to find out phytoconstituents which have potency to inhibit specific target of novel corona virus. Methods: We had perform molecular docking studies on three different proteins of novel corona virus namely COVID-19 main protease (3CL pro), papain-like protease (PL pro) and spike protein (S) attached to ACE2 binding domain. The screening of the phytoconstituents on the basis of binding affinity compared to standard drugs. The validations of screened compounds were done using ADMET and bioactivity prediction. Results: We had screened five compounds biscoclaurine, norreticuline, amentoflavone, licoricidin and myricetin using insilico approach. All compounds found safe in insilico toxicity studies. Bioactivity prediction reviles that these all compounds may act through protease or enzyme inhibition. Results of compound biscoclaurine norreticuline were more interesting as this biscoclaurine had higher binding affinity for the target 3CLpro and PLpro targets and norreticuline had higher binding affinity for the target PLpro and Spike protein. Conclusion: Our study concludes that these compounds could be further explored rapidly as it may have potential to fight against COVID-19.

Carbohydrate-Binding Agents: Potential of Repurposing for COVID-19 Therapy

2020 ◽  
Vol 21 (11) ◽  
pp. 1085-1096 ◽  
Author(s):  
Rajesh Kumar Gupta ◽  
Girish R. Apte ◽  
Kiran Bharat Lokhande ◽  
Satyendra Mishra ◽  
Jayanta K. Pal
Keyword(s):  
Vaccine Development ◽  
Host Cells ◽  
Carbohydrate Binding ◽  
Atypical Pneumonia ◽  
The Novel ◽  
High Infection ◽  
Binding Agents ◽  
Current Scenario ◽  
Antiviral Activities ◽  
Novel Drug

: With the emergence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the whole world is suffering from atypical pneumonia, which resulted in more than 559,047 deaths worldwide. In this time of crisis and urgency, the only hope comes from new candidate vaccines and potential antivirals. However, formulating new vaccines and synthesizing new antivirals are a laborious task. Therefore, considering the high infection rate and mortality due to COVID-19, utilization of previous information, and repurposing of existing drugs against valid viral targets have emerged as a novel drug discovery approach in this challenging time. The transmembrane spike (S) glycoprotein of coronaviruses (CoVs), which facilitates the virus’s entry into the host cells, exists in a homotrimeric form and is covered with N-linked glycans. S glycoprotein is known as the main target of antibodies having neutralizing potency and is also considered as an attractive target for therapeutic or vaccine development. Similarly, targeting of N-linked glycans of S glycoprotein envelope of CoV via carbohydrate-binding agents (CBAs) could serve as an attractive therapeutic approach for developing novel antivirals. CBAs from natural sources like lectins from plants, marine algae and prokaryotes and lectin mimics like Pradimicin-A (PRM-A) have shown antiviral activities against CoV and other enveloped viruses. However, the potential use of CBAs specifically lectins was limited due to unfavorable responses like immunogenicity, mitogenicity, hemagglutination, inflammatory activity, cellular toxicity, etc. Here, we reviewed the current scenario of CBAs as antivirals against CoVs, presented strategies to improve the efficacy of CBAs against CoVs; and studied the molecular interactions between CBAs (lectins and PRM-A) with Man9 by molecular docking for potential repurposing against CoVs in general, and SARSCoV- 2, in particular.

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