Displaying publications 21 - 40 of 97 in total

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  1. Antiviral actions of flavanoid-derived compounds on dengue virus type-2
    Muhamad M, Kee LY, Rahman NA, Yusof R
    Int J Biol Sci, 2010 May 23;6(3):294-302.
    PMID: 20567498
    Dengue viruses, mosquito-borne members of the Flaviviridae family, are the causative agents of dengue fever and its associated complications, dengue haemorrhagic fever and dengue shock syndrome. To date, more than 2.5 billion people in over 100 countries are at risk of infection, and approximately 20 million infections were reported annually. There is currently no treatment or vaccine available for dengue infection. This study employed a whole-cell organism model or in vitro methods to study the inhibitory property of the flavanoid-derived compounds against DENV2 activity. Results showed that at concentration not exceeding the maximum non-toxic dose (MNTD), these compounds completely prevented DENV2 infection in HepG2 cells as indicated by the absence of cytophatic effects. The in vitro antiviral activity assessed in HepG2 cells employing virus inhibition assay showed high inhibitory activity in a dose dependent manner. At concentration below MNTD, compounds exhibited inhibitory activity against DENV2 with a range of potency strengths of 72% to 100%. The plaque forming unit per ml (pfu/ml) was reduced prominently with a maximum reduction of 98% when the infected HepG2 cells were treated with the highest non-toxic dose of compounds. The highly potent activity of the compounds against DENV2 infection strongly suggests their potential as a lead antiviral agent for dengue.
  2. Fulltext Fusion of protegrin-1 and plectasin to MAP30 shows significant inhibition activity against dengue virus replication
    Rothan HA, Bahrani H, Mohamed Z, Abd Rahman N, Yusof R
    PLoS One, 2014;9(4):e94561.
    PMID: 24722532 DOI: 10.1371/journal.pone.0094561
    Dengue virus (DENV) broadly disseminates in tropical and sub-tropical countries and there are no vaccine or anti-dengue drugs available. DENV outbreaks cause serious economic burden due to infection complications that requires special medical care and hospitalization. This study presents a new strategy for inexpensive production of anti-DENV peptide-fusion protein to prevent and/or treat DENV infection. Antiviral cationic peptides protegrin-1 (PG1) and plectasin (PLSN) were fused with MAP30 protein to produce recombinant antiviral peptide-fusion protein (PG1-MAP30-PLSN) as inclusion bodies in E. coli. High yield production of PG1-MAP30-PLSN protein was achieved by solubilization of inclusion bodies in alkaline buffer followed by the application of appropriate refolding techniques. Antiviral PG1-MAP30-PLSN protein considerably inhibited DENV protease (NS2B-NS3pro) with half-maximal inhibitory concentration (IC50) 0.5±0.1 μM. The real-time proliferation assay (RTCA) and the end-point proliferation assay (MTT assay) showed that the maximal-nontoxic dose of the peptide-fusion protein against Vero cells is approximately 0.67±0.2 μM. The cell-based assays showed considerable inhibition of the peptide-fusion protein against binding and proliferating stages of DENV2 into the target cells. The peptide-fusion protein protected DENV2-challeged mice with 100% of survival at the dose of 50 mg/kg. In conclusion, producing recombinant antiviral peptide-fusion protein by combining short antiviral peptide with a central protein owning similar activity could be useful to minimize the overall cost of short peptide production and take advantage of its synergistic antiviral activities.
  3. Fulltext An analytical approach to evaluate the performance of graphene and carbon nanotubes for NH3 gas sensor applications
    Akbari E, Arora VK, Enzevaee A, Ahmadi MT, Saeidmanesh M, Khaledian M, et al.
    Beilstein J Nanotechnol, 2014;5:726-34.
    PMID: 24991510 DOI: 10.3762/bjnano.5.85
    Carbon, in its variety of allotropes, especially graphene and carbon nanotubes (CNTs), holds great potential for applications in variety of sensors because of dangling π-bonds that can react with chemical elements. In spite of their excellent features, carbon nanotubes (CNTs) and graphene have not been fully exploited in the development of the nanoelectronic industry mainly because of poor understanding of the band structure of these allotropes. A mathematical model is proposed with a clear purpose to acquire an analytical understanding of the field-effect-transistor (FET) based gas detection mechanism. The conductance change in the CNT/graphene channel resulting from the chemical reaction between the gas and channel surface molecules is emphasized. NH3 has been used as the prototype gas to be detected by the nanosensor and the corresponding current-voltage (I-V) characteristics of the FET-based sensor are studied. A graphene-based gas sensor model is also developed. The results from graphene and CNT models are compared with the experimental data. A satisfactory agreement, within the uncertainties of the experiments, is obtained. Graphene-based gas sensor exhibits higher conductivity compared to that of CNT-based counterpart for similar ambient conditions.
  4. Fulltext Protegrin-1 inhibits dengue NS2B-NS3 serine protease and viral replication in MK2 cells
    Rothan HA, Abdulrahman AY, Sasikumer PG, Othman S, Rahman NA, Yusof R
    J Biomed Biotechnol, 2012;2012:251482.
    PMID: 23093838 DOI: 10.1155/2012/251482
    Dengue diseases have an economic as well as social burden worldwide. In this study, the antiviral activity of protegrin-1 (PG-1, RGGRLCYCRRRFCVCVGR) peptide towards dengue NS2B-NS3pro and viral replication in Rhesus monkey kidney (MK2) cells was investigated. The peptide PG-1 was synthesized by solid-phase peptide synthesis, and disulphide bonds formation followed by peptide purification was confirmed by LC-MS and RPHPLC. Dengue NS2B-NS3pro was produced as a single-chain recombinant protein in E. coli. The NS2B-NS3pro assay was carried out by measuring the florescence emission of catalyzed substrate. Real-time PCR was used to evaluate the inhibition potential of PG-1 towards dengue serotype-2 (DENV-2) replication in MK2 cells. The results showed that PG-1 inhibited dengue NS2B-NS3pro at IC(50) of 11.7 μM. The graded concentrations of PG-1 at nontoxic range were able to reduce viral replication significantly (P < 0.001) at 24, 48, and 72 hrs after viral infection. However, the percentage of inhibition was significantly (P < 0.01) higher at 24 hrs compared to 48 and 72 hrs. These data show promising therapeutic potential of PG-1 against dengue infection, hence it warrants further analysis and improvement of the peptide features as a prospective starting point for consideration in designing attractive dengue virus inhibitors.
  5. Fulltext Boesenbergia rotunda: From Ethnomedicine to Drug Discovery
    Eng-Chong T, Yean-Kee L, Chin-Fei C, Choon-Han H, Sher-Ming W, Li-Ping CT, et al.
    Evid Based Complement Alternat Med, 2012;2012:473637.
    PMID: 23243448 DOI: 10.1155/2012/473637
    Boesenbergia rotunda is a herb from the Boesenbergia genera under the Zingiberaceae family. B. rotunda is widely found in Asian countries where it is commonly used as a food ingredient and in ethnomedicinal preparations. The popularity of its ethnomedicinal usage has drawn the attention of scientists worldwide to further investigate its medicinal properties. Advancement in drug design and discovery research has led to the development of synthetic drugs from B. rotunda metabolites via bioinformatics and medicinal chemistry studies. Furthermore, with the advent of genomics, transcriptomics, proteomics, and metabolomics, new insights on the biosynthetic pathways of B. rotunda metabolites can be elucidated, enabling researchers to predict the potential bioactive compounds responsible for the medicinal properties of the plant. The vast biological activities exhibited by the compounds obtained from B. rotunda warrant further investigation through studies such as drug discovery, polypharmacology, and drug delivery using nanotechnology.
  6. Fulltext Anxiety in Frontline and Non-Frontline Healthcare Providers in Kelantan, Malaysia
    Mohd Noor N, Che Yusof R, Yacob MA
    Int J Environ Res Public Health, 2021 Jan 20;18(3).
    PMID: 33498397 DOI: 10.3390/ijerph18030861
    In response to the coronavirus disease 2019 (COVID-19) pandemic, healthcare providers are exposed to psychological and mental health implications, including vicarious traumatization, anxiety, and depression. Gradual increases in the number of COVID-19 cases meant they were inadequately protected from contamination due to a shortage of protective equipment, excessive workloads, emotional exhaustion and frustration. These circumstances affect their work performance in delivering health services. This study aims to compare the levels of anxiety in frontline and non-frontline healthcare providers during the COVID-19 pandemic. This study applied a comparative cross-sectional design between May and July 2020 at the Hospital Raja Perempuan Zainab II. Convenient sampling was applied in the selection of eligible participants. The case report form contained two self-administered questionnaires, namely, The Hospital Anxiety and Depression Scale and Medical Outcome Study Social Support Survey. Descriptive analysis, analysis of variance, and analysis of covariance were conducted using SPSS version 26. The number of participants recruited was 306, including 160 healthcare providers in the frontline group and 146 in the non-frontline group. The non-frontline healthcare providers reported a significantly higher anxiety mean score of 1.7 than the frontline providers after adjusting for gender, duration of employment, and social support. It indicates that non-frontline healthcare providers require psychological support similar to that of frontline healthcare providers during the COVID-19 pandemic.
  7. Fulltext HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block
    Nor Rashid N, Yong ZL, Yusof R, Watson RJ
    Virol J, 2016 Jan 04;13:2.
    PMID: 26728921 DOI: 10.1186/s12985-015-0460-8
    Retinoblastoma like protein 2 (RBL2) or p130 is a member of the pocket protein family, which is infrequently mutated in human tumours. Its expression is posttranscriptionally regulated and largely G0 restricted. We have previously shown that E6/E7 oncoproteins encoded by human papillomavirus (HPV) type 16, which is a high-risk type for cervical cancer development, must target p130 to promote the host cell to exit from quiescence (G0) state and enter S phase of the cell cycle. P130 is associated with the DREAM (DP, RB-like, E2F and MuvB) complex in G0/G1, which prevents S phase progression by repressing transcription of E2F-regulated genes. E7 proteins could potentially disrupt the p130-DREAM complex through two known mechanisms: direct interaction with p130 or induction of cyclin dependent kinase 2 (CDK2) phosphorylation by interacting with its inhibitor, p21(CIP1).
  8. A B-myb--DREAM complex is not critical to regulate the G2/M genes in HPV-transformed cell lines
    Rashid NN, Yusof R, Watson RJ
    Anticancer Res, 2014 Nov;34(11):6557-63.
    PMID: 25368258
    It is well-established that HPV E7 proteins, encoded by human papillomavirus (HPV) genes, frequently associated with cervical cancers bind avidly to the retinoblastoma (RB) family of pocket proteins and disrupt their association with members of the E2F transcription factor family. Our previous study showed that the repressive p130-dimerization partner, RB-like, E2F and multi-vulval class (DREAM) complex was disrupted by HPV16 E7 proteins in order to maintain the viral replication in CaSki cells. However, we would like to address whether the activator B-myb-DREAM complex is critical in regulating the replication and mitosis phase since our previous study showed increased B-myb-DREAM expression in HPV-transformed cell lines when compared to control cells.
  9. Disruption of repressive p130-DREAM complexes by human papillomavirus 16 E6/E7 oncoproteins is required for cell-cycle progression in cervical cancer cells
    Nor Rashid N, Yusof R, Watson RJ
    J Gen Virol, 2011 Nov;92(Pt 11):2620-2627.
    PMID: 21813705 DOI: 10.1099/vir.0.035352-0
    Human papillomaviruses (HPVs) with tropism for mucosal epithelia are the major aetiological factors in cervical cancer. Most cancers are associated with so-called high-risk HPV types, in particular HPV16, and constitutive expression of the HPV16 E6 and E7 oncoproteins is critical for malignant transformation in infected keratinocytes. E6 and E7 bind to and inactivate the cellular tumour suppressors p53 and Rb, respectively, thus delaying differentiation and inducing proliferation in suprabasal keratinocytes to enable HPV replication. One member of the Rb family, p130, appears to be a particularly important target for E7 in promoting S-phase entry. Recent evidence indicates that p130 regulates cell-cycle progression as part of a large protein complex termed DREAM. The composition of DREAM is cell cycle-regulated, associating with E2F4 and p130 in G0/G1 and with the B-myb transcription factor in S/G2. In this study, we addressed whether p130-DREAM is disrupted in HPV16-transformed cervical cancer cells and whether this is a critical function for E6/E7. We found that p130-DREAM was greatly diminished in HPV16-transformed cervical carcinoma cells (CaSki and SiHa) compared with control cell lines; however, when E6/E7 expression was targeted by specific small hairpin RNAs, p130-DREAM was reformed and the cell cycle was arrested. We further demonstrated that the profound G1 arrest in E7-depleted CaSki cells was dependent on p130-DREAM reformation by also targeting the expression of the DREAM component Lin-54 and p130. The results show that continued HPV16 E6/E7 expression is necessary in cervical cancer cells to prevent cell-cycle arrest by a repressive p130-DREAM complex.
  10. 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.
  11. Fulltext Development of a NS2B/NS3 protease inhibition assay using AlphaScreen® beads for screening of anti-dengue activities
    Abduraman MA, Hariono M, Yusof R, Rahman NA, Wahab HA, Tan ML
    Heliyon, 2018 Dec;4(12):e01023.
    PMID: 30560214 DOI: 10.1016/j.heliyon.2018.e01023
    Background: Dengue infection is an endemic infectious disease and it can lead to dengue fever, dengue hemorrhagic fever, and/or dengue shock syndromes. Dengue NS2B/NS3 protease complex is essential for viral replication and is a primary target for anti-dengue drug development. In this study, a NS2B/NS3 protease inhibition assay was developed using AlphaScreen® beads and was used to screen compounds for their protease inhibition activities.

    Methods: The assay system utilized a known NS2B/NS3 peptide substrate, a recombinant of NS2B/NS3 protease with proprietary StrepTactin® donor and nickel chelate acceptor beads in 384-well format.

    Results: The optimized assay to screen for NS2B/NS3 protease inhibitors was demonstrated to be potentially useful with reasonable z' factor, coefficient variance and signal to background ratio. However, screening of synthesized thioguanine derivatives using the optimized AlphaScreen® assay revealed weak NS2B/NS3 inhibition activities.

    Conclusion: The AlphaScreen® assay to screen for NS2B/NS3 protease inhibitors is potentially applicable for high throughput screening.

  12. Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors
    Takhi M, Sreenivas K, Reddy CK, Munikumar M, Praveena K, Sudheer P, et al.
    Eur J Med Chem, 2014 Sep 12;84:382-94.
    PMID: 25036796 DOI: 10.1016/j.ejmech.2014.07.036
    A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
  13. Fulltext Polycaprolactone Triol-Citrate Scaffolds Enriched with Human Platelet Releasates Promote Chondrogenic Phenotype and Cartilage Extracellular Matrix Formation
    Rothan HA, Mahmod SA, Djordjevic I, Golpich M, Yusof R, Snigh S
    Tissue Eng Regen Med, 2017 Apr;14(2):93-101.
    PMID: 30603466 DOI: 10.1007/s13770-017-0023-8
    In this paper we report the differentiating properties of platelet-rich plasma releasates (PRPr) on human chondrocytes within elastomeric polycaprolactone triol-citrate (PCLT-CA) porous scaffold. Human-derived chondrocyte cellular content of glycosaminoglycans (GAGs) and total collagen were determined after seeding into PCLT-CA scaffold enriched with PRPr cells. Immunostaining and real time PCR was applied to evaluate the expression levels of chondrogenic and extracellular gene markers. Seeding of chondrocytes into PCLT-CA scaffold enriched with PRPr showed significant increase in total collagen and GAGs production compared with chondrocytes grown within control scaffold without PRPr cells. The mRNA levels of collagen II and SOX9 increased significantly while the upregulation in Cartilage Oligomeric Matrix Protein (COMP) expression was statistically insignificant. We also report the reduction of the expression levels of collagen I and III in chondrocytes as a consequence of proximity to PRPr cells within the scaffold. Interestingly, the pre-loading of PRPr caused an increase of expression levels of following extracellular matrix (ECM) proteins: fibronectin, laminin and integrin β over the period of 3 days. Overall, our results introduce the PCLT-CA elastomeric scaffold as a new system for cartilage tissue engineering. The method of PRPr cells loading prior to chondrocyte culture could be considered as a potential environment for cartilage tissue engineering as the differentiation and ECM formation is enhanced significantly.
  14. Fulltext Novel trajectory clustering method based on distance dependent Chinese restaurant process
    Arfa R, Yusof R, Shabanzadeh P
    PeerJ Comput Sci, 2019;5:e206.
    PMID: 33816859 DOI: 10.7717/peerj-cs.206
    Trajectory clustering and path modelling are two core tasks in intelligent transport systems with a wide range of applications, from modeling drivers' behavior to traffic monitoring of road intersections. Traditional trajectory analysis considers them as separate tasks, where the system first clusters the trajectories into a known number of clusters and then the path taken in each cluster is modelled. However, such a hierarchy does not allow the knowledge of the path model to be used to improve the performance of trajectory clustering. Based on the distance dependent Chinese restaurant process (DDCRP), a trajectory analysis system that simultaneously performs trajectory clustering and path modelling was proposed. Unlike most traditional approaches where the number of clusters should be known, the proposed method decides the number of clusters automatically. The proposed algorithm was tested on two publicly available trajectory datasets, and the experimental results recorded better performance and considerable improvement in both datasets for the task of trajectory clustering compared to traditional approaches. The study proved that the proposed method is an appropriate candidate to be used for trajectory clustering and path modelling.
  15. Fulltext Phytoestrogen (Daidzein) Promotes Chondrogenic Phenotype of Human Chondrocytes in 2D and 3D Culture Systems
    Mahmod SA, Snigh S, Djordjevic I, Mei Yee Y, Yusof R, Ramasamy TS, et al.
    Tissue Eng Regen Med, 2017 Apr;14(2):103-112.
    PMID: 30603467 DOI: 10.1007/s13770-016-0004-3
    Clinical investigations have shown a significant relationship between osteoarthritis (OA) and estrogens levels in menopausal women. Therefore, treatment with exogenous estrogens has been shown to decrease the risk of OA. However, the effect estrogen has not been clearly demonstrated in the chondrocytes using phytoestrogens, which lack the specific side-effects of estrogens, may provide an alternative therapy. This study was designed to examine the possible effects of phytoestrogen (daidzein) on human chondrocyte phenotype and extracellular matrix formation. Phytoestrogens which lack the specific side-effects of estrogens may provide beneficial effect without causing hormone based side effect. Human chondrocytes cells were cultured in 2D (flask) and 3D (PCL-CA scaffold) systems. Daidzein cytotoxic effect was determined by MTT assay. Chondrocyte cellular content of glycosaminoglycans (GAGs), total collagen and chondrogenic gene expression were determined in both culture systems after treatment with daidzein. Daidzein showed time-dependent and dose-independent effects on chondrocyte bioactivity. The compound at low doses showed significant (p  0.05). The expression levels of Fibronectin, Laminin and Integrin β1 were significantly increased especially in 3D culture system. This study was illustrated the potential positive effects of daidzein on maintenance of human chondrocyte phenotype and extracellular matrix formation suggesting an attractive and viable alternative therapy for OA.
  16. Antiviral and virucidal activities of sulphated polysaccharides against Japanese encephalitis virus
    Nor Rashid N, Yusof R, Rothan HA
    Trop Biomed, 2020 Sep 01;37(3):713-721.
    PMID: 33612784 DOI: 10.47665/tb.37.3.713
    Japanese encephalitis virus (JEV), a member of the family Flaviviridae, causes severe neurological disorders in humans. JEV infections represent one of the most widely spread mosquito-borne diseases, and therefore, it has been considered as an endemic disease. An effective antiviral drug is still unavailable to treat JEV, and current drugs only provide supportive treatment to alleviate the symptoms and stabilize patients' conditions. This study was designed to evaluate the antiviral activity of the sulphated polysaccharides "Carrageenan," a linear sulphated polysaccharide that is extracted from red edible seaweeds against JEV replication in vitro. Viral inactivation, attachment, and post-infection assays were used to determine the mode of inhibition of Carrageenan. Virus titters after each application were evaluated by plaque formation assay. MTT assay was used to determine the 50% cytotoxic concentration (CC50), and ELISA-like cell-based assay and immunostaining and immunostaining techniques were used to evaluate the 50% effective concentration (EC50). This study showed that Carrageenan inhibited JEV at an EC50 of 15 µg/mL in a dose-dependent manner with CC50 more than 200 µg/mL in healthy human liver cells (WRL68). The mode of inhibition assay showed that the antiviral effects of Carrageenan are mainly due to their ability to inhibit the early stages of virus infection such as the viral attachment and the cellular entry stages. Our investigation showed that Carrageenan could be considered as a potent antiviral agent to JEV infection. Further experimental and clinical studies are needed to investigate the potential applications of Carrageenan for clinical intervention against JEV infection.
  17. Evaluation of neutralizing antibodies produced by papaya mosaic virus nanoparticles fused to the E2EP3 peptide epitope of Chikungunya envelope
    Nor Rashid N, Teoh TC, Al-Harbi SJ, Yusof R, Rothan HA
    Trop Biomed, 2021 Mar 01;38(1):36-41.
    PMID: 33797522 DOI: 10.47665/tb.38.1.007
    Chikungunya virus (CHIKV) infection is the cause of acute symptoms and chronic symmetrical polyarthritis associated with long-term morbidity and mortality. Currently, there is no available licensed vaccine or particularly useful drug for human use against CHIKV infection. This study was conducted to evaluate the efficacy of antibodies produced by papaya mosaic virus (PapMV) nanoparticles fused to E2EP3 peptide of CHIKV envelope as a recombinant CHIKV vaccine. PapMV, PapMV-C- E2EP3, and E2EP3-N-PapMV were produced in E. coli with an approximate size of 27 to 30 kDa. ICR mice (5 to 6 weeks of age) were injected subcutaneously with 25 micrograms of vaccine construct, and ELISA measured the titer of CHIKV specific IgG antibodies. The results showed that both recombinant proteins E2EP3-N-PapMV and PapMVC-E2EP3 were able to induce IgG antibodies production in immunized mice against CHIKV while immunization with recombinant PapMV showed no IgG antibodies induction. The neutralizing activity of the antibodies generated by either E2EP3-N-PapMV or PapMV-C-E2EP3 exhibited similar inhibition to CHIKV replication in Vero cells using the cells based antibody neutralizing assay and analyzed by plaque formation assay. This study showed the effectiveness of nanoparticles vaccine generated by fusing epitope peptide of CHIKV envelope to papaya mosaic virus envelope in inducing a robust immune response in mice against CHIKV. The data showed that levels of neutralizing antibodies correlate with a protective immune response CHIKV replication.
  18. Discovery of small molecule inhibitors against the NS3/4A serine protease of Hepatitis C virus genotype 3 via highthroughput virtual screening and in vitro evaluations
    Sakhor W, Teoh TC, Yusof R, Lim SK, Razif MFM
    Trop Biomed, 2020 Sep 01;37(3):609-625.
    PMID: 33612776 DOI: 10.47665/tb.37.3.609
    The hepatitis C virus (HCV) consists of eight genotypes and 90 subtypes, with genotype (GT) 3 being the second most common globally and is linked to higher incidences of steatosis and rapid development of fibrosis and cirrhosis. The NS3/4A serine protease, a heterodimer complex of two HCV non-structural proteins, is an effective target for pharmaceutical intervention due to its essential roles in processing HCV polyproteins and inhibiting innate immunity. This study combines structure-based virtual screening (SBVS) of predefined compound libraries, pharmacokinetic prediction (ADME/T) and in vitro evaluation to identify potential low molecular weight (<500 Dalton) inhibitors of the NS3/4A serine protease (GT3). In silico screening of ZINC and PubChem libraries yielded five selected compounds as potential candidates. Dose-dependent inhibition of the NS3/4A serine protease and HCV replication in HuH-7.5 cells revealed that compound A (PubChem ID No. 16672637) exhibited inhibition towards HCV GT3 with an IC50 of 106.7µM and EC50 of 25.8µM, respectively. Thus, compound A may be developed as a potent, low molecular weight drug against the HCV NS3/4A serine protease of GT3.
  19. Current approaches in antiviral drug discovery against the Flaviviridae family
    Baharuddin A, Hassan AA, Sheng GC, Nasir SB, Othman S, Yusof R, et al.
    Curr Pharm Des, 2014;20(21):3428-44.
    PMID: 24001228
    Viruses belonging to the Flaviviridae family primarily spread through arthropod vectors, and are the major causes of illness and death around the globe. The Flaviviridae family consists of 3 genera which include the Flavivirus genus (type species, yellow fever virus) as the largest genus, the Hepacivirus (type species, hepatitis C virus) and the Pestivirus (type species, bovine virus diarrhea). The flaviviruses (Flavivirus genus) are small RNA viruses transmitted by mosquitoes and ticks that take over host cell machinery in order to propagate. However, hepaciviruses and pestiviruses are not antropod-borne. Despite the extensive research and public health concern associated with flavivirus diseases, to date, there is no specific treatment available for any flavivirus infections, though commercially available vaccines for yellow fever, Japanese encephalitis and tick-born encephalitis exist. Due to the global threat of viral pandemics, there is an urgent need for new drugs. In many countries, patients with severe cases of flavivirus infections are treated only by supportive care, which includes intravenous fluids, hospitalization, respiratory support, and prevention of secondary infections. This review discusses the strategies used towards the discovery of antiviral drugs, focusing on rational drug design against Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Yellow Fever virus (YFV) and Hepatitis C virus (HCV). Only modified peptidic, nonpeptidic, natural compounds and fragment-based inhibitors (typically of mass less than 300 Da) against structural and non-structural proteins are discussed.
  20. Docking of noncompetitive inhibitors into dengue virus type 2 protease: understanding the interactions with allosteric binding sites
    Othman R, Kiat TS, Khalid N, Yusof R, Newhouse EI, Newhouse JS, et al.
    J Chem Inf Model, 2008 Aug;48(8):1582-91.
    PMID: 18656912 DOI: 10.1021/ci700388k
    A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.
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