Displaying all 11 publications

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  1. Duncan CJ, Mohamad SM, Young DF, Skelton AJ, Leahy TR, Munday DC, et al.
    Sci Transl Med, 2015 Sep 30;7(307):307ra154.
    PMID: 26424569 DOI: 10.1126/scitranslmed.aac4227
    Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.
    Matched MeSH terms: Antiviral Agents/metabolism*
  2. Shalayel MH, Al-Mazaideh GM, Aladaileh SH, Al-Swailmi FK, Al-Thiabat MG
    Pak J Pharm Sci, 2020 Sep;33(5):2179-2186.
    PMID: 33824127
    Novel coronavirus disease (COVID-19) has become a pandemic threat to public health. Vaccines and targeted therapeutics to prevent infections and stop virus proliferation are currently lacking. Endoribonuclease Nsp15 plays a vital role in the life cycle, including replication and transcription as well as virulence of the virus. Here, we investigated Vitamin D for its in silico potential inhibition of the binding sites of SARS-CoV-2 endoribonuclease Nsp15. In this study, we selected Remdesivir, Chloroquine, Hydroxychloroquine and Vitamin D to study the potential binding affinity with the putative binding sites of endoribonuclease Nsp15 of COVID-19. The docking study was applied to rationalize the possible interactions of the target compounds with the active site of endoribonuclease Nsp 15. Among the results, Vitamin D was found to have the highest potency with strongest interaction in terms of LBE, lowest RMSD, and lowest inhibition intensity Ki than the other standard compounds. The investigation results of endoribonuclease Nsp15 on the PrankWeb server showed that there are three prospective binding sites with the ligands. The singularity of Vitamin D interaction with the three pockets, particularly in the second pocket, may write down Vitamin D as a potential inhibitor of COVID-19 Nsp15 endoribonuclease binding sites and favour addition of Vitamin D in the treatment plan for COVID-19 alone or in combination with the other used drugs in this purpose, which deserves exploration in further in vitro and in vivo studies.
    Matched MeSH terms: Antiviral Agents/metabolism
  3. Saoin S, Wisitponchai T, Intachai K, Chupradit K, Moonmuang S, Nangola S, et al.
    Asian Pac J Allergy Immunol, 2018 06;36(2):126-135.
    PMID: 28802032 DOI: 10.12932/AP-280217-0037
    BACKGROUND: AnkGAG1D4 is an artificial ankyrin repeat protein which recognizes the capsid protein (CA) of the human immunodeficiency virus type 1 (HIV-1) and exhibits the intracellular antiviral activity on the viral assembly process. Improving the binding affinity of AnkGAG1D4 would potentially enhance the AnkGAG1D4-mediated antiviral activity.

    OBJECTIVE: To augment the affinity of AnkGAG1D4 scaffold towards its CA target, through computational predictions and experimental designs.

    METHOD: Three dimensional structure of the binary complex formed by AnkGAG1D4 docked to the CA was used as a model for van der Waals (vdW) binding energy calculation. The results generated a simple guideline to select the amino acids for modifications. Following the predictions, modified AnkGAG1D4 proteins were produced and further evaluated for their CA-binding activity, using ELISA-modified method and bio-layer interferometry (BLI).

    RESULTS: Tyrosine at position 56 (Y56) in AnkGAG1D4 was experimentally identified as the most critical residue for CA binding. Rational substitutions of this residue diminished the binding affinity. However, vdW calculation preconized to substitute serine for tyrosine at position 45. Remarkably, the affinity for the viral CA was significantly enhanced in AnkGAG1D4-S45Y mutant, with no alteration of the target specificity.

    CONCLUSIONS: The S-to-Y mutation at position 45, based on the prediction of interacting amino acids and on vdW binding energy calculation, resulted in a significant enhancement of the affinity of AnkGAG1D4 ankyrin for its CA target. AnkGAG1D4-S45Y mutant represented the starting point for further construction of variants with even higher affinity towards the viral CA, and higher therapeutic potential in the future.

    Matched MeSH terms: Antiviral Agents/metabolism
  4. Yusuf M, Mohamed N, Mohamad S, Janezic D, Damodaran KV, Wahab HA
    J Chem Inf Model, 2016 Jan 25;56(1):82-100.
    PMID: 26703840 DOI: 10.1021/acs.jcim.5b00331
    Increased reports of oseltamivir (OTV)-resistant strains of the influenza virus, such as the H274Y mutation on its neuraminidase (NA), have created some cause for concern. Many studies have been conducted in the attempt to uncover the mechanism of OTV resistance in H274Y NA. However, most of the reported studies on H274Y focused only on the drug-bound system, so the direct effects of the mutation on NA itself prior to drug binding still remain unclear. Therefore, molecular dynamics simulations of NA in apo form, followed by principal component analysis and interaction energy calculations, were performed to investigate the structural changes of the NA binding site as a result of the H274Y mutation. It was observed that the disruption of the NA binding site due to the H274Y mutation was initiated by the repulsive effect of Y274 on the 250-loop, which in turn altered the hydrogen-bonding network around residue 274. The rotated W295 side chain caused the upward movement of the 340-loop. Consequently, sliding box docking results suggested that the binding pathway of OTV was compromised because of the disruption of this binding site. This study also highlighted the importance of the functional group at C6 of the sialic acid mimicry. It is hoped that these results will improve the understanding of OTV resistance and shed some light on the design of a novel anti-influenza drug.
    Matched MeSH terms: Antiviral Agents/metabolism
  5. Paul A, Tang TH, Ng SK
    Front Immunol, 2018;9:1831.
    PMID: 30147694 DOI: 10.3389/fimmu.2018.01831
    Interferon regulatory factor 9 (IRF9) is an integral transcription factor in mediating the type I interferon antiviral response, as part of the interferon-stimulated gene factor 3. However, the role of IRF9 in many important non-communicable diseases has just begun to emerge. The duality of IRF9's role in conferring protection but at the same time exacerbates diseases is certainly puzzling. The regulation of IRF9 during these conditions is not well understood. The high homology of IRF9 DNA-binding domain to other IRFs, as well as the recently resolved IRF9 IRF-associated domain structure can provide the necessary insights for progressive inroads on understanding the regulatory mechanism of IRF9. This review sought to outline the structural basis of IRF9 that guides its regulation and interaction in antiviral immunity and other diseases.
    Matched MeSH terms: Antiviral Agents/metabolism*
  6. Umareddy I, Tang KF, Vasudevan SG, Devi S, Hibberd ML, Gu F
    J Gen Virol, 2008 Dec;89(Pt 12):3052-3062.
    PMID: 19008393 DOI: 10.1099/vir.0.2008/001594-0
    Outbreaks of dengue disease are constant threats to tropical and subtropical populations but range widely in severity, from mild to haemorrhagic fevers, for reasons that are still elusive. We investigated the interferon (IFN) response in infected human cell lines A549 and HepG2, using two strains (NGC and TSV01) of dengue serotype 2 (DEN2) and found that the two viruses exhibited a marked difference in inducing type I IFN response. While TSV01 infection led to activation of type I antiviral genes such as EIF2AK2 (PKR), OAS, ADAR and MX, these responses were absent in NGC-infected cells. Biochemical analysis revealed that NGC but not TSV01 suppressed STAT-1 and STAT-2 activation in response to type I IFN (alpha and beta). However, these two strains did not differ in their response to type II IFN (gamma). Although unable to suppress IFN signalling, TSV01 infection caused a weaker IFN-beta induction compared with NGC, suggesting an alternative mechanism of innate immune escape. We extended our study to clinical isolates of various serotypes and found that while MY10245 (DEN2) and MY22713 (DEN4) could suppress the IFN response in a similar fashion to NGC, three other strains of dengue [EDEN167 (DEN1), MY02569 (DEN1) and MY10340 (DEN2)] were unable to suppress the IFN response, suggesting that this difference is strain-dependent but not serotype-specific. Our report indicates the existence of a strain-specific virulence factor that may impact on disease severity.
    Matched MeSH terms: Antiviral Agents/metabolism
  7. Haghani A, Mehrbod P, Safi N, Kadir FA, Omar AR, Ideris A
    BMC Complement Altern Med, 2017 Jan 05;17(1):22.
    PMID: 28056926 DOI: 10.1186/s12906-016-1498-x
    Edible Bird's Nest (EBN) as a popular traditional Chinese medicine is believed to have health enhancing and antiviral activities against influenza A virus (IAV); however, the molecular mechanism behind therapeutic effects of EBN is not well characterized.
    Matched MeSH terms: Antiviral Agents/metabolism
  8. Yusuf M, Konc J, Sy Bing C, Trykowska Konc J, Ahmad Khairudin NB, Janezic D, et al.
    J Chem Inf Model, 2013 Sep 23;53(9):2423-36.
    PMID: 23980878 DOI: 10.1021/ci400421e
    ProBiS is a new method to identify the binding site of protein through local structural alignment against the nonredundant Protein Data Bank (PDB), which may result in unique findings compared to the energy-based, geometry-based, and sequence-based predictors. In this work, binding sites of Hemagglutinin (HA), which is an important target for drugs and vaccines in influenza treatment, have been revisited by ProBiS. For the first time, the identification of conserved binding sites by local structural alignment across all subtypes and strains of HA available in PDB is presented. ProBiS finds three distinctive conserved sites on HA's structure (named Site 1, Site 2, and Site 3). Compared to other predictors, ProBiS is the only one that accurately defines the receptor binding site (Site 1). Apart from that, Site 2, which is located slightly above the TBHQ binding site, is proposed as a potential novel conserved target for membrane fusion inhibitor. Lastly, Site 3, located around Helix A at the stem domain and recently targeted by cross-reactive antibodies, is predicted to be conserved in the latest H7N9 China 2013 strain as well. The further exploration of these three sites provides valuable insight in optimizing the influenza drug and vaccine development.
    Matched MeSH terms: Antiviral Agents/metabolism
  9. Abdul Ahmad SA, Palanisamy UD, Tejo BA, Chew MF, Tham HW, Syed Hassan S
    Virol J, 2017 11 21;14(1):229.
    PMID: 29162124 DOI: 10.1186/s12985-017-0895-1
    BACKGROUND: The rapid rise and spread in dengue cases, together with the unavailability of safe vaccines and effective antiviral drugs, warrant the need to discover and develop novel anti-dengue treatments. In this study the antiviral activity of geraniin, extracted from the rind of Nephelium lappaceum, against dengue virus type-2 (DENV-2) was investigated.

    METHODS: Geraniin was prepared from Nephelium lappaceum rind by reverse phase C-18 column chromatography. Cytotoxicity of geraniin towards Vero cells was evaluated using MTT assay while IC50 value was determined by plaque reduction assay. The mode-of-action of geraniin was characterized using the virucidal, attachment, penetration and the time-of-addition assays'. Docking experiments with geraniin molecule and the DENV envelope (E) protein was also performed. Finally, recombinant E Domain III (rE-DIII) protein was produced to physiologically test the binding of geraniin to DENV-2 E-DIII protein, through ELISA competitive binding assay.

    RESULTS: Cytotoxicity assay confirmed that geraniin was not toxic to Vero cells, even at the highest concentration tested. The compound exhibited DENV-2 plaque formation inhibition, with an IC50 of 1.75 μM. We further revealed that geraniin reduced viral infectivity and inhibited DENV-2 from attaching to the cells but had little effect on its penetration. Geraniin was observed to be most effective when added at the early stage of DENV-2 infection. Docking experiments showed that geraniin binds to DENV E protein, specifically at the DIII region, while the ELISA competitive binding assay confirmed geraniin's interaction with rE-DIII with high affinity.

    CONCLUSIONS: Geraniin from the rind of Nephelium lappaceum has antiviral activity against DENV-2. It is postulated that the compound inhibits viral attachment by binding to the E-DIII protein and interferes with the initial cell-virus interaction. Our results demonstrate that geraniin has the potential to be developed into an effective antiviral treatment, particularly for early phase dengue viral infection.

    Matched MeSH terms: Antiviral Agents/metabolism
  10. Chin VK, Atika Aziz NA, Hudu SA, Harmal NS, Syahrilnizam A, Jalilian FA, et al.
    J Virol Methods, 2016 10;236:117-125.
    PMID: 27432115 DOI: 10.1016/j.jviromet.2016.07.012
    Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection in infants and young children globally and is a significant pathogen of the elderly and immunocompromised. The M2-2 protein of respiratory syncytial virus (RSV) is particularly important in regulation of viral RNA transcription and replication that could be a potential anti-viral candidate against RSV infection. In this study, we designed and validated siRNAs that specifically target the RSV M2-2 gene. Four siRNAs targeting different regions of the M2-2 gene were designed using web tool. In-vitro evaluation of silencing effect was performed by using RSV infected Vero cell line. Viral M2-2 linked GFP recombinant plasmid was co-transfected with non-targeted siRNA, Pooled siRNA, siRNA 1, siRNA 2, siRNA 3 and siRNA 4 using synthetic cationic polymer. The silencing effect of M2-2 gene at the protein level was measured both qualitatively and quantitatively by using fluorescence microscopy and flow cytometry. Meanwhile, the silencing effect at the mRNA level was assessed by using RT-qPCR. This study showed that all four designed siRNAs can effectively and efficiently silence M2-2 gene. siRNA 2 showed the highest (98%) silencing effect on protein level and siRNA 4 with 83.1% at the mRNA level. The viral assay showed no significant cytopathic effects observed after 6days post-infection with siRNAs. In conclusion, this study showed the effectiveness of siRNA in silencing M2-2 gene both at the protein and mRNA level which could potentially be used as a novel therapeutic agent in the treatment of RSV infection. However, further study is warranted to investigate the silencing effect of M2-2 protein and inhibition of RSV infection.
    Matched MeSH terms: Antiviral Agents/metabolism*
  11. Rothan HA, Mohamed Z, Suhaeb AM, Rahman NA, Yusof R
    OMICS, 2013 Nov;17(11):560-7.
    PMID: 24044366 DOI: 10.1089/omi.2013.0056
    Dengue virus infects millions of people worldwide, and there is no vaccine or anti-dengue therapeutic available. Antimicrobial peptides have been shown to possess effective antiviral activity against various viruses. One of the main limitations of developing these peptides as potent antiviral drugs is the high cost of production. In this study, high yield production of biologically active plectasin peptide was inexpensively achieved by producing tandem plectasin peptides as inclusion bodies in E. coli. Antiviral activity of the recombinant peptide towards dengue serotype-2 NS2B-NS3 protease (DENV2 NS2B-NS3pro) was assessed as a target to inhibit dengue virus replication in Vero cells. Single units of recombinant plectasin were collected after applying consecutive steps of refolding, cleaving by Factor Xa, and nickel column purification to obtain recombinant proteins of high purity. The maximal nontoxic dose (MNTD) of the recombinant peptide against Vero cells was 20 μM (100 μg/mL). The reaction velocity of DENV2 NS2B-NS3pro decreased significantly after increasing concentrations of recombinant plectasin were applied to the reaction mixture. Plectasin peptide noncompetitively inhibited DENV2 NS2B-NS3pro at Ki value of 5.03 ± 0.98 μM. The percentage of viral inhibition was more than 80% at the MNTD value of plectasin. In this study, biologically active recombinant plectasin which was able to inhibit dengue protease and viral replication in Vero cells was successfully produced in E. coli in a time- and cost- effective method. These findings are potentially important in the development of potent therapeutics against dengue infection.
    Matched MeSH terms: Antiviral Agents/metabolism
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