Displaying publications 101 - 120 of 154 in total

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  1. Fulltext Virucidal activity of Garcinia parvifolia leaf extracts in animal cell culture
    Adnan A, Allaudin ZN, Hani H, Loh HS, Khoo TJ, Ting KN, et al.
    BMC Complement Altern Med, 2019 Jul 10;19(1):169.
    PMID: 31291936 DOI: 10.1186/s12906-019-2586-5
    BACKGROUND: Garcinia species contain bioactive compounds such as flavonoids, xanthones, triterpernoids, and benzophenones with antibacterial, antifungal, anti-inflammatory, and antioxidant activities. In addition, many of these compounds show interesting biological properties such as anti-human immunodeficiency virus activity. Garcinia parvifolia is used in traditional medicine. Currently, the antiviral activity of G. parvifolia is not known.

    METHODS: This study was conducted to determine the effects of ethyl acetate (45 L Ea), ethanol (45 L Et), and hexane (45 L H) leaf extracts of G. parvifolia on the infectivity of pseudorabies virus (PrV) in Vero cells. The antiviral effects of the extracts were determined by cytopathic effect (CPE), inhibition, attachment, and virucidal assays.

    RESULTS: The 50% cytotoxicity concentration (CC50) values obtained were 237.5, 555.0, and 

    Matched MeSH terms: Antiviral Agents/pharmacology*
  2. H274Y's Effect on Oseltamivir Resistance: What Happens Before the Drug Enters the Binding Site
    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/pharmacology
  3. Fulltext Evaluation of antiviral activities of four local Malaysian Phyllanthus species against herpes simplex viruses and possible antiviral target
    Tan WC, Jaganath IB, Manikam R, Sekaran SD
    Int J Med Sci, 2013;10(13):1817-29.
    PMID: 24324358 DOI: 10.7150/ijms.6902
    Nucleoside analogues such as acyclovir are effective antiviral drugs against herpes simplex virus infections since its introduction. However, with the emergence of acyclovir-resistant HSV strains particularly in immunocompromised patients, there is a need to develop an alternative antiherpetic drug and plants could be the potential lead. In this study, the antiviral activity of the aqueous extract of four Phyllanthus species were evaluated against herpes simplex virus type-1 (HSV-1) and HSV-2 in Vero cells by quantitative PCR. The protein expressions of untreated and treated infected Vero cells were studied by 2D-gel electrophoresis and Western blot. This is the first study that reported the antiviral activity of P. watsonii. P. urinaria was shown to demonstrate the strongest antiviral activity against HSV-1 and HSV-2, with SI >33.6. Time-of-addition studies suggested that the extract may act against the early infection stage and the replication stage. Protein expression studies indicated that cellular proteins that are involved in maintaining cytoskeletal structure could be potential target for development of antiviral drugs. Preliminary findings indicated that P. urinaria demonstrated potent inhibitory activity against HSV. Hence, further studies such as in vivo evaluation are required for the development of effective antiherpetic drug.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  4. Fulltext Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus
    Lim SV, Rahman MB, Tejo BA
    BMC Bioinformatics, 2011;12 Suppl 13:S24.
    PMID: 22373153 DOI: 10.1186/1471-2105-12-S13-S24
    The dengue virus is the most significant arthropod-borne human pathogen, and an increasing number of cases have been reported over the last few decades. Currently neither vaccines nor drugs against the dengue virus are available. NS5 methyltransferase (MTase), which is located on the surface of the dengue virus and assists in viral attachment to the host cell, is a promising antiviral target. In order to search for novel inhibitors of NS5 MTase, we performed a computer-aided virtual screening of more than 5 million commercially available chemical compounds using two approaches: i) structure-based screening using the crystal structure of NS5 MTase and ii) ligand-based screening using active ligands of NS5 MTase. Structure-based screening was performed using the LIDAEUS (LIgand Discovery At Edinburgh UniverSity) program. The ligand-based screening was carried out using the EDULISS (EDinburgh University LIgand Selection System) program.
    Matched MeSH terms: Antiviral Agents/pharmacology
  5. Fulltext Attenuation of influenza virus infectivity with herbal-marine compound (HESA-A): an in vitro study in MDCK cells
    Mehrbod P, Ideris A, Omar AR, Hair-Bejo M, Tan SW, Kheiri MT, et al.
    Virol J, 2012;9:44.
    PMID: 22340010 DOI: 10.1186/1743-422X-9-44
    The influenza virus is still one of the most important respiratory risks affecting humans which require effective treatments. In this case, traditional medications are of interest. HESA-A is an active natural biological compound from herbal-marine origin. Previous studies have reported that the therapeutic properties of HESA-A are able to treat psoriasis vulgaris and cancers. However, no antiviral properties have been reported.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  6. Fulltext Novel antiviral activity of baicalein against dengue virus
    Zandi K, Teoh BT, Sam SS, Wong PF, Mustafa MR, Abubakar S
    BMC Complement Altern Med, 2012;12:214.
    PMID: 23140177 DOI: 10.1186/1472-6882-12-214
    Dengue is a serious arboviral disease currently with no effective antiviral therapy or approved vaccine available. Therefore, finding the effective compound against dengue virus (DENV) replication is very important. Among the natural compounds, bioflavonoids derived mainly from plants are of interest because of their biological and medicinal benefits.
    Matched MeSH terms: Antiviral Agents/pharmacology
  7. Design, synthesis, and evaluation of thiazolidinone derivatives as antimicrobial and anti-viral agents
    Ravichandran V, Jain A, Kumar KS, Rajak H, Agrawal RK
    Chem Biol Drug Des, 2011 Sep;78(3):464-70.
    PMID: 21615706 DOI: 10.1111/j.1747-0285.2011.01149.x
    A series of 1,3-thiazolidin-4-one derivatives were prepared by the reaction of respective aromatic amine, aromatic aldehyde, and thioglycolic acid in dry benzene/toluene. The newly synthesized compounds were characterized on the basis of elemental analysis, IR, (1) HNMR, and mass spectra. The newly synthesized final compounds were evaluated for their in vitro antibacterial, antifungal, and anti-viral activities. Preliminary results indicated that some of the compounds demonstrated antibacterial activity in the range of 7-13 μg/mL, antifungal activity in the range of 13-17 μg/mL, comparable with the standard drugs, ciprofloxacin and fluconazole. Structure-activity relationship studies revealed that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus had a significant impact on the in vitro antimicrobial and anti-viral activity of these classes of agents.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  8. Fulltext Antiviral activity of four types of bioflavonoid against dengue virus type-2
    Zandi K, Teoh BT, Sam SS, Wong PF, Mustafa MR, Abubakar S
    Virol J, 2011;8:560.
    PMID: 22201648 DOI: 10.1186/1743-422X-8-560
    Dengue is a major mosquito-borne disease currently with no effective antiviral or vaccine available. Effort to find antivirals for it has focused on bioflavonoids, a plant-derived polyphenolic compounds with many potential health benefits. In the present study, antiviral activity of four types of bioflavonoid against dengue virus type -2 (DENV-2) in Vero cell was evaluated. Anti-dengue activity of these compounds was determined at different stages of DENV-2 infection and replication cycle. DENV replication was measured by Foci Forming Unit Reduction Assay (FFURA) and quantitative RT-PCR. Selectivity Index value (SI) was determined as the ratio of cytotoxic concentration 50 (CC50) to inhibitory concentration 50 (IC50) for each compound.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  9. Fulltext Screening of anti-dengue activity in methanolic extracts of medicinal plants
    Tang LI, Ling AP, Koh RY, Chye SM, Voon KG
    BMC Complement Altern Med, 2012;12:3.
    PMID: 22244370 DOI: 10.1186/1472-6882-12-3
    Dengue fever regardless of its serotypes has been the most prevalent arthropod-borne viral diseases among the world population. The development of a dengue vaccine is complicated by the antibody-dependent enhancement effect. Thus, the development of a plant-based antiviral preparation promises a more potential alternative in combating dengue disease.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  10. Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes
    Hurt AC, Selleck P, Komadina N, Shaw R, Brown L, Barr IG
    Antiviral Res, 2007 Mar;73(3):228-31.
    PMID: 17112602
    Since 2003, highly pathogenic A(H5N1) influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. A group of 55 influenza A(H5N1) viruses isolated from various regions of South East Asia between 2004 and 2006 were tested for their susceptibility to the anti-influenza drugs the neuraminidase inhibitors and adamantanes. The majority of strains were found to be fully sensitive to the neuraminidase inhibitors oseltamivir carboxylate, zanamivir and peramivir; however two strains demonstrated increased IC50 values. Sequence analysis of these strains revealed mutations in the normally highly conserved residues 116 and 117 of the N1 neuraminidase. Sequence analysis of the M2 gene showed that all of the A(H5N1) viruses from Vietnam, Malaysia and Cambodia contained mutations (L26I and S31N) associated with resistance to the adamantane drugs (rimantadine and amantadine), while strains from Indonesia were found to be a mix of both adamantane resistant (S31N) and sensitive viruses. None of the A(H5N1) viruses from Myanmar contained mutations known to confer adamantane resistance. These results support the use of neuraminidase inhibitors as the most appropriate class of antiviral drug to prevent or treat human A(H5N1) virus infections.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  11. A monoclonal antibody to ameliorate central nervous system infection and improve survival in a murine model of human Enterovirus-A71 encephalomyelitis
    Tan SH, Ong KC, Perera D, Wong KT
    Antiviral Res, 2016 Aug;132:196-203.
    PMID: 27340013 DOI: 10.1016/j.antiviral.2016.04.015
    BACKGROUND: Enterovirus A71 (EV-A71) encephalomyelitis is an often fatal disease for which there is no specific treatment available. Passive immunization with a specific monoclonal antibody to EV-A71 was used on a murine model of EV-A71 encephalomyelitis to evaluate its therapeutic effectiveness before and after established central nervous system (CNS) infection.

    METHODS: Mice were intraperitoneally-infected with a mouse-adapted EV-A71 strain and treated with a dose of monoclonal antibody (MAb) daily for 3 days on day 1, 2 and 3 post-infection or for 3 days on 3, 4 and 5 post-infection. Treatment effectiveness was evaluated by signs of infection and survival rate. Histopathology and qPCR analyses were performed on mice sacrificed a day after completing treatment.

    RESULTS: In mock-treated mice, CNS infection was established from day 3 post-infection. All mice treated before established CNS infection, survived and recovered completely without CNS infection. All mice treated after established CNS infection survived with mild paralysis, and viral load and antigens/RNA at day 6 post-infection were significantly reduced.

    CONCLUSIONS: Passive immunization with our MAb could prevent CNS infection in mice if given early before the establishment of CNS infection. It could also ameliorate established CNS infection if optimal and repeated doses were given.

    Matched MeSH terms: Antiviral Agents/pharmacology*
  12. Fulltext Potential Antiviral Agents from Marine Fungi: An Overview
    Moghadamtousi SZ, Nikzad S, Kadir HA, Abubakar S, Zandi K
    Mar Drugs, 2015 Jul;13(7):4520-38.
    PMID: 26204947 DOI: 10.3390/md13074520
    Biodiversity of the marine world is only partially subjected to detailed scientific scrutiny in comparison to terrestrial life. Life in the marine world depends heavily on marine fungi scavenging the oceans of lifeless plants and animals and entering them into the nutrient cycle by. Approximately 150 to 200 new compounds, including alkaloids, sesquiterpenes, polyketides, and aromatic compounds, are identified from marine fungi annually. In recent years, numerous investigations demonstrated the tremendous potential of marine fungi as a promising source to develop new antivirals against different important viruses, including herpes simplex viruses, the human immunodeficiency virus, and the influenza virus. Various genera of marine fungi such as Aspergillus, Penicillium, Cladosporium, and Fusarium were subjected to compound isolation and antiviral studies, which led to an illustration of the strong antiviral activity of a variety of marine fungi-derived compounds. The present review strives to summarize all available knowledge on active compounds isolated from marine fungi with antiviral activity.
    Matched MeSH terms: Antiviral Agents/pharmacology
  13. Fulltext Antiviral activity of silymarin against chikungunya virus
    Lani R, Hassandarvish P, Chiam CW, Moghaddam E, Chu JJ, Rausalu K, et al.
    Sci Rep, 2015;5:11421.
    PMID: 26078201 DOI: 10.1038/srep11421
    The mosquito-borne chikungunya virus (CHIKV) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. Although there are several studies to evaluate the efficacy of drugs against CHIKV, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. Here, we investigated the antiviral activity of three types of flavonoids against CHIKV in vitro replication. Three compounds: silymarin, quercetin and kaempferol were evaluated for their in vitro antiviral activities against CHIKV using a CHIKV replicon cell line and clinical isolate of CHIKV of Central/East African genotype. A cytopathic effect inhibition assay was used to determine their activities on CHIKV viral replication and quantitative reverse transcription PCR was used to calculate virus yield. Antiviral activity of effective compound was further investigated by evaluation of CHIKV protein expression using western blotting for CHIKV nsP1, nsP3, and E2E1 proteins. Briefly, silymarin exhibited significant antiviral activity against CHIKV, reducing both CHIKV replication efficiency and down-regulating production of viral proteins involved in replication. This study may have important consequence for broaden the chance of getting the effective antiviral for CHIKV infection.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  14. Fulltext A combination of doxycycline and ribavirin alleviated chikungunya infection
    Rothan HA, Bahrani H, Mohamed Z, Teoh TC, Shankar EM, Rahman NA, et al.
    PLoS One, 2015;10(5):e0126360.
    PMID: 25970853 DOI: 10.1371/journal.pone.0126360
    Lack of vaccine and effective antiviral drugs against chikungunya virus (CHIKV) outbreaks have led to significant impact on health care in the developing world. Here, we evaluated the antiviral effects of tetracycline (TETRA) derivatives and other common antiviral agents against CHIKV. Our results showed that within the TETRA derivatives group, Doxycycline (DOXY) exhibited the highest inhibitory effect against CHIKV replication in Vero cells. On the other hand, in the antiviral group Ribavirin (RIBA) showed higher inhibitory effects against CHIKV replication compared to Aciclovir (ACIC). Interestingly, RIBA inhibitory effects were also higher than all but DOXY within the TETRA derivatives group. Docking studies of DOXY to viral cysteine protease and E2 envelope protein showed non-competitive interaction with docking energy of -6.6±0.1 and -6.4±0.1 kcal/mol respectively. The 50% effective concentration (EC50) of DOXY and RIBA was determined to be 10.95±2.12 μM and 15.51±1.62 μM respectively, while DOXY+RIBA (1:1 combination) showed an EC50 of 4.52±1.42 μM. When compared, DOXY showed higher inhibition of viral infectivity and entry than RIBA. In contrast however, RIBA showed higher inhibition against viral replication in target cells compared to DOXY. Assays using mice as animal models revealed that DOXY+RIBA effectively inhibited CHIKV replication and attenuated its infectivity in vivo. Further experimental and clinical studies are warranted to investigate their potential application for clinical intervention of CHIKV disease.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  15. Genomic variations among wildtype and mutant strains of pseudorabies virus
    Zeenathul NA, Mohd-Azmi ML, Ali AS, Aini I, Sheik-Omar AR, Abdul-Rahim AM, et al.
    Rev. Argent. Microbiol., 2002 Jan-Mar;34(1):7-14.
    PMID: 11942085
    Both wild-type virulent and mutant strains of pseudorabies virus (PrV) were used in this study. Mutants used were derived from the plaque purified strain PrVmAIP. A total of six drug resistant mutants, three bromodeoxyuridine (BUdR) resistant and three iododeoxyuridine (IUdR) resistant, respectively, were isolated and passaged in chicken embryo fibroblast (CEF) cells. The DNA of these PrVs were compared with the wild-type isolates by means of the restriction fragment pattern (RFP) findings produced with Bam HI, Kpn I, Hind III and Bgl II restriction enzymes (RE). Compared to the wild-type PrVs (PrV-VBA1-parental strain of PrVmAIP; PrV-VBA2; PrV-VBA3), the RFP of PrVmAIP showed the presence of mutations within the RE sites studied. Both PrV-VBA1 and PrV-VBA2 appeared to be closely related but their RFPs differed from PrV-VBA3. Significant differences either in the number, size or migrations of the DNA fragments could also be detected in the BUdR resistant strains. Even though different features of cytopathic effect (GPE) were observed in the IUdR resistant PrVs, the RFP findings remained identical. The PrVs studied showed considerable differences from the reference PrV (PrV-CD).
    Matched MeSH terms: Antiviral Agents/pharmacology
  16. Fulltext Pharmacophore modelling of vanillin derivatives, favipiravir, chloroquine, hydroxychloroquine, monolaurin and tetrodotoxin as MPro inhibitors of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
    Law WY, Asaruddin MR, Bhawani SA, Mohamad S
    BMC Res Notes, 2020 Nov 11;13(1):527.
    PMID: 33176880 DOI: 10.1186/s13104-020-05379-6
    OBJECTIVES: The aim of this study was to use Ligand-based pharmacophore modelling approach for four established antiviral drugs, namely remdesivir, lopinavir, ritonavir and hydroxychloroquine for COVID-19 inhibitors as training sets. In this study Twenty vanillin derivatives together with monolaurin and tetrodotoxin were used as test sets to evaluate as potential SARS-CoV-2 inhibitors. The Structure-based pharmacophore modelling approach was also performed using 5RE6, 5REX and 5RFZ in order to analyse the binding site and ligand-protein complex interactions.

    RESULTS: The pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition.

    Matched MeSH terms: Antiviral Agents/pharmacology*
  17. Fulltext Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling
    Hariono M, Choi SB, Roslim RF, Nawi MS, Tan ML, Kamarulzaman EE, et al.
    PLoS One, 2019;14(1):e0210869.
    PMID: 30677071 DOI: 10.1371/journal.pone.0210869
    Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  18. Fulltext Structure-Based Design of Antivirals against Envelope Glycoprotein of Dengue Virus
    Anasir MI, Ramanathan B, Poh CL
    Viruses, 2020 03 26;12(4).
    PMID: 32225021 DOI: 10.3390/v12040367
    Dengue virus (DENV) presents a significant threat to global public health with more than 500,000 hospitalizations and 25,000 deaths annually. Currently, there is no clinically approved antiviral drug to treat DENV infection. The envelope (E) glycoprotein of DENV is a promising target for drug discovery as the E protein is important for viral attachment and fusion. Understanding the structure and function of DENV E protein has led to the exploration of structure-based drug discovery of antiviral compounds and peptides against DENV infections. This review summarizes the structural information of the DENV E protein with regards to DENV attachment and fusion. The information enables the development of antiviral agents through structure-based approaches. In addition, this review compares the potency of antivirals targeting the E protein with the antivirals targeting DENV multifunctional enzymes, repurposed drugs and clinically approved antiviral drugs. None of the current DENV antiviral candidates possess potency similar to the approved antiviral drugs which indicates that more efforts and resources must be invested before an effective DENV drug materializes.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  19. High-Throughput Screening Assays for Dengue Antiviral Drug Development
    Jabanathan SG, Xuan LZ, Ramanathan B
    Methods Mol Biol, 2021;2296:279-302.
    PMID: 33977455 DOI: 10.1007/978-1-0716-1358-0_17
    Dengue is an arthropod-borne viral disease that has become endemic and a global threat in over 100 countries. The increase in prevalence would require a long-term measure to control outbreaks. Sanofi Pasteur has licensed the tetravalent dengue vaccine (Dengvaxia) in certain dengue endemic countries. However, the efficacy of the vaccine is limited against certain dengue serotypes and can only be used for individuals from the age from 9 to 45 years old. Over the years, there has been intense research conducted on the development of antivirals against dengue virus (DENV) through either inhibiting the virus replication or targeting the host cell mechanism to block the virus entry. However, no approved antiviral drug against dengue is yet available. In this chapter, we describe the dengue antiviral development workflow including (i) prophylactic, (ii) virucidal, and (iii) postinfection assays that are employed in the antiviral drug screening process against DENV. Further, we demonstrate different methods that can be used to enumerate the reduction in virus foci number including foci-forming unit reduction assay (FFURA), estimation of viral RNA copy number through quantitative real-time PCR, and a high-throughput enzyme linked immunosorbent assay (ELISA)-based quantification of virus particles.
    Matched MeSH terms: Antiviral Agents/pharmacology*
  20. Fulltext Small molecule grp94 inhibitors block dengue and Zika virus replication
    Rothan HA, Zhong Y, Sanborn MA, Teoh TC, Ruan J, Yusof R, et al.
    Antiviral Res, 2019 11;171:104590.
    PMID: 31421166 DOI: 10.1016/j.antiviral.2019.104590
    Two major flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), cause severe health and economic burdens worldwide. Recently, genome-wide screenings have uncovered the importance of regulators of the Hrd1 ubiquitin ligase-mediated endoplasmic reticulum (ER)-associated degradation (ERAD) pathway for flavivirus replication in host cells. Here we report the identification of the compound Bardoxolone methyl (CDDO-me) as a potent inhibitor of the Hrd1 ubiquitin ligase-mediated ERAD, which possesses a broad-spectrum activity against both DENV and ZIKV. Cellular thermal shift assay (CETSA) suggested that CDDO-me binds to grp94, a key component of the Hrd1 pathway, at a low nanomolar concentration, whereas interaction was not detected with its paralog Hsp90. CDDO-me and the grp94 inhibitor PU-WS13 substantially suppressed DENV2 replication and the cytopathic effects caused by DENV and ZIKV infection. The antiviral activities of both compounds were demonstrated for all four DENV serotypes and four ZIKV strains in multiple human cell lines. This study defines grp94 as a crucial host factor for flavivirus replication and identified CDDO-me as a potent small molecule inhibitor of flavivirus infection. Inhibition of grp94 may contribute to the antiviral activity of CDDO-me. Further investigation of grp94 inhibitors may lead to a new class of broad-spectrum anti-flaviviral medications.
    Matched MeSH terms: Antiviral Agents/pharmacology*
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