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Fulltext Finding Lead Compounds for Dengue Antivirals from a Collection of Old Drugs through In Silico Target Prediction and Subsequent In Vitro Validation

Abdullah ZL, Chee HY, Yusof R, Mohd Fauzi F

ACS Omega, 2023 Sep 12;8(36):32483-32497.
PMID: 37720780 DOI: 10.1021/acsomega.3c02607

Dengue virus (DENV) infection is one of the most widely spread flavivirus infections. Despite the fatality it could cause, no antiviral treatment is currently available to treat the disease. Hence, this study aimed to repurpose old drugs as novel DENV NS3 inhibitors. Ligand-based (L-B) and proteochemometric (PCM) prediction models were built using 62,354 bioactivity data to screen for potential NS3 inhibitors. Selected drugs were then subjected to the foci forming unit reduction assay (FFURA) and protease inhibition assay. Finally, molecular docking was performed to validate these results. The in silico studies revealed that both models performed well in the internal and external validations. However, the L-B model showed better accuracy in the external validation in terms of its sensitivity (0.671). In the in vitro validation, all drugs (zileuton, trimethadione, and linalool) were able to moderately inhibit the viral activities at the highest concentration tested. Zileuton showed comparable results with linalool when tested at 2 mM against the DENV NS3 protease, with a reduction of protease activity at 17.89 and 18.42%, respectively. Two new compounds were also proposed through the combination of the selected drugs, which are ziltri (zilueton + trimethadione) and zilool (zileuton + linalool). The molecular docking study confirms the in vitro observations where all drugs and proposed compounds were able to achieve binding affinity ≥ -4.1 kcal/mol, with ziltri showing the highest affinity at -7.7 kcal/mol, surpassing the control, panduratin A. The occupation of both S1 and S2 subpockets of NS2B-NS3 may be essential and a reason for the lower binding energy shown by the proposed compounds compared to the screened drugs. Based on the results, this study provided five potential new lead compounds (ziltri, zilool, zileuton, linalool, and trimethadione) for DENV that could be modified further.
Fulltext Arteriovenous Malformation Hemorrhage in Pregnancy: A Systematic Review and Meta-Analysis

Che Yusof R, Norhayati MN, Mohd Azman Y

Int J Environ Res Public Health, 2022 Oct 13;19(20).
PMID: 36293763 DOI: 10.3390/ijerph192013183

Hemorrhage of arteriovenous malformation (AVM) is a rare condition during pregnancy. This study was proposed to pool the proportion of AVM hemorrhage per pregnancy. A systematic review and meta-analysis with three databases were performed to review the studies published until April 2022. The Newcastle Ottawa Scale was used for risk assessment of data quality. The meta-analysis was conducted by a generic inverse variance of double arcsine transformation with a random model using Stata software. Twelve studies were included in this review. The pooled proportion of AVM hemorrhage per pregnancy was 0.16 (95% CI: 0.08, 0.26). The subgroup analyses were carried out based on world regions and study designs, and the study duration with the highest proportion of each subgroup was Europe [0.35 (95% CI: 0.02, 0.79)], with retrospective review [0.18 (95% CI: 007, 0.32)] and 10 to 20 years of study duration [0.37 (95% CI: 0.06, 0.77)]. The AVM hemorrhage per pregnancy in this review was considered low. However, the conclusion must be carefully interpreted since this review had a small study limitation.
Fulltext Effectiveness of school-based child sexual abuse intervention among school children in the new millennium era: Systematic review and meta-analyses

Che Yusof R, Norhayati MN, Mohd Azman Y

Front Public Health, 2022;10:909254.
PMID: 35937243 DOI: 10.3389/fpubh.2022.909254

INTRODUCTION: School-based child sexual abuse intervention programs were developed to educate the school children to protect them from sexual abuse. The programs were evaluated to make sure the interventions were effective in reducing child sexual abuse cases (CSA). This review aimed to determine the effectiveness of the school-based child sexual abuse intervention programs in the new millennium era (2000-2021) in improving the knowledge, skills, and attitude of school children under 18 years old toward child sexual abuse.
METHODS: A systematic search was conducted through MEDLINE (PubMed), EBSCO, and SCOPUS databases to collect full English articles related to school-based CSA intervention programs published from 2000 to 2021.
RESULTS: A total of 29 studies from randomized control trial and quasi-experimental from several countries was analyzed. Comparisons within group of pre-post intervention for knowledge, skills, and attitude were measured by standardized mean difference (SMD) and 95% CI of -1.06 (95% CI: -1.29, -0.84), -0.91 (95% CI: -1.2, -0.61), and -0.51 (95% CI: -3.61, 0.58), respectively. Meanwhile for between intervention and control group comparisons, the SMD of knowledge was 0.9 (95% CI: 0.63, 1.18), skills was 0.39 (95% CI: 0.07, 0.71), and attitude was 1.76 (95% CI: 0.46, 3.07).
CONCLUSION: The programs were found to be effective in improving the knowledge, skills, and attitude of the students from pre-intervention to post-intervention and between the intervention and control groups.Systematic Review Registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022312383, identifier: CRD42022312383.
Fulltext Prevalence of Psychological Impacts on Healthcare Providers during COVID-19 Pandemic in Asia

Norhayati MN, Che Yusof R, Azman MY

Int J Environ Res Public Health, 2021 Aug 30;18(17).
PMID: 34501747 DOI: 10.3390/ijerph18179157

COVID-19 has impacted people psychologically globally, including healthcare providers. Anxiety, depression, and stress are the most common impacts that have affected these people. Thus, this study was aimed to ascertain the estimated prevalence of psychological impacts among healthcare providers in the Asian region. A systematic search was performed in the MEDLINE, CINAHL, and Scopus databases for original research articles published between 2020 and April 2021. Only studies published in English were included. The quality of data was assessed using the Joanna Briggs Institute Meta-Analysis, and the analysis was performed using generic inverse variance with a random-effects model by Review Manager software. A total of 80 studies across 18 countries in Asia region were pooled to assess the data prevalence on anxiety (34.81% (95% CI: 30.80%, 38.83%)), depression (34.61% (95% CI: 30.87%, 38.36%)), stress (31.72% (95% CI: 21.25%, 42.18%)), insomnia (37.89% (95% CI: 25.43%, 50.35%)), and post-traumatic stress disorder (15.29% (95% CI: 11.43%, 19.15%)). Subgroup analyses were conducted across regions, type of healthcare providers, sex, and occupation. This review has identified a high prevalence of anxiety, depression, stress, and insomnia but a low prevalence of post-traumatic stress disorder among healthcare providers in Asia regions. Effective intervention support programs are urgently needed to improve psychological health of healthcare providers and maintaining the health system.
Binding of tetrabutylammonium bromide based deep eutectic solvent to DNA by spectroscopic analysis

Yusof R, Jumbri K, Ahmad H, Abdulmalek E, Abdul Rahman MB

Spectrochim Acta A Mol Biomol Spectrosc, 2021 May 15;253:119543.
PMID: 33636491 DOI: 10.1016/j.saa.2021.119543

The binding characteristics of DNA in deep eutectic solvents (DESs), particularly the binding energy and interaction mechanism, are not widely known. In this study, the binding of tetrabutylammonium bromide (TBABr) based DES of different hydrogen bond donors (HBD), including ethylene glycol (EG), glycerol (Gly), 1,3-propanediol (1,3-PD) and 1,5-pentanediol (1,5-PD), to calf thymus DNA was investigated using fluorescence spectroscopy. It was found that the shorter the alkyl chain length (2 carbons) and higher EG ratios of TBABr:EG (1:5) increased the binding constant (Kb) between DES and DNA up to 5.75 × 105 kJ mol-1 and decreased the binding of Gibbs energy (ΔGo) to 32.86 kJ mol-1. Through displacement studies, all synthesised DESs have been shown to displace DAPI (4',6-diamidino-2-phenylindole) and were able to bind on the minor groove of Adenine-Thymine (AT)-rich DNA. A higher number of hydroxyl (OH) groups caused the TBABr:Gly to form more hydrogen bonds with DNA bases and had the highest ability to quench DAPI from DNA, with Stern-Volmer constants (Ksv) of 115.16 M-1. This study demonstrated that the synthesised DESs were strongly bound to DNA through a combination of electrostatic, hydrophobic, and groove binding. Hence, DES has the potential to solvate and stabilise nucleic acid structures.
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.
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.
Rational drug discovery: Ellagic acid as a potent dual-target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes

Lim SK, Othman R, Yusof R, Heh CH

Chem Biol Drug Des, 2021 01;97(1):28-40.
PMID: 32657543 DOI: 10.1111/cbdd.13756

Structure-based virtual screening (SBVS) has served as a popular strategy for rational drug discovery. In this study, we aimed to discover novel benzopyran-based inhibitors that targeted the NS3 enzymes (NS3/4A protease and NS3 helicase) of HCV G3 using a combination of in silico and in vitro approaches. With the aid of SBVS, six novel compounds were discovered to inhibit HCV G3 NS3/4A protease and two phytochemicals (ellagic acid and myricetin) were identified as dual-target inhibitors that inhibited both NS3/4A protease and NS3 helicase in vitro (IC50 = 40.37 ± 5.47 nm and 6.58 ± 0.99 µm, respectively). Inhibitory activities against the replication of HCV G3 replicons were further assessed in a cell-based system with four compounds showed dose-dependent inhibition. Compound P8 was determined to be the most potent compound from the cell-based assay with an EC50 of 19.05 µm. The dual-target inhibitor, ellagic acid, was determined as the second most potent (EC50 = 32.37 µm) and the most selective in its inhibitory activity against the replication of HCV replicons, without severely affecting the viability of the host cells (selectivity index > 6.18).
Fulltext Vicarious traumatization in healthcare providers in response to COVID-19 pandemic in Kelantan, Malaysia

Norhayati MN, Che Yusof R, Azman MY

PLoS One, 2021;16(6):e0252603.
PMID: 34086747 DOI: 10.1371/journal.pone.0252603

BACKGROUND: In the fight against the COVID-19 pandemic, frontline healthcare providers who are engaged in the direct diagnosis, treatment, and care of patients face a high risk of infection yet receive inadequate protection from contamination and minimal support to cope with overwork, frustration, and exhaustion. These problems have created significant psychological and mental health concerns for frontline healthcare providers. This study aimed to compare the levels of vicarious traumatization between frontline and non-frontline healthcare providers in response to the COVID-19 pandemic.
METHODOLOGY: All the subjects who met the inclusion criteria were recruited for this comparative cross-sectional study, which was conducted from May to July 2020 in two hospitals in Kelantan, Malaysia. A self-administered questionnaire, namely, the Malay-version Vicarious Traumatization Questionnaire and the Medical Outcome Study Social Support Survey were utilized. A descriptive analysis, independent t-test, and analysis of covariance were performed using SPSS Statistics version 26.
RESULTS: A total of 160 frontline and 146 non-frontline healthcare providers were recruited. Vicarious traumatization was significantly higher among the non-frontline healthcare providers (estimated marginal mean [95% CI]: 79.7 [75.12, 84.30]) compared to the frontline healthcare providers (estimated marginal mean [95% CI]: 74.3 [68.26, 80.37]) after adjusting for sex, duration of employment, and social support.
CONCLUSION: The level of vicarious traumatization was higher among non-frontline compared to frontline healthcare providers. However, the level of severity may differ from person to person, depending on how they handle their physical, psychological, and mental health. Hence, support from various resources, such as colleagues, family, the general public, and the government, may play an essential role in the mental health of healthcare providers.
Fulltext Depressive symptoms among frontline and non-frontline healthcare providers in response to the COVID-19 pandemic in Kelantan, Malaysia: A cross sectional study

Norhayati MN, Che Yusof R, Azman MY

PLoS One, 2021;16(8):e0256932.
PMID: 34464399 DOI: 10.1371/journal.pone.0256932

BACKGROUND: Healthcare providers are vulnerable in the fight against COVID-19 and may experience significant psychological and mental health consequences. This study aimed to compare the levels of depressive symptoms among frontline and non-frontline healthcare providers in response to the COVID-19 pandemic.
METHODS: A comparative cross-sectional study was conducted in two government hospitals managing COVID-19-related cases in Kelantan, Malaysia from May to July 2020 to identify and compared depressive symptoms levels of frontline and non-frontline healthcare providers. Convenient sampling was applied in the selection of eligible participants and those diagnosed as having any psychiatric illnesses were excluded. The self-administered questionnaires for the Malay versions of the Hospital Anxiety and Depression Scale to measure depressive symptoms score and the Medical Outcome Study Social Support Survey to measure social support score as an important confounder. A descriptive analysis, independent t-test and ANCOVA were performed using SPSS version 26.
RESULTS: A total of 306 respondents from healthcare providers were recruited which 160 were frontline healthcare providers and 146 were non-frontline healthcare providers. The level of depressive symptoms (HADS score >8) was 27.5% for the frontline healthcare providers and 37.7% for the non-frontline healthcare providers. The mean depressive symptoms score for the non-frontline healthcare providers was 0.75 points higher than that of the frontline healthcare providers after adjusting for gender, duration of employment and social support.
CONCLUSION: Non-frontline healthcare providers are also experiencing psychological distress during the COVID-19 pandemic even though they do not have direct contact with COVID-19 patients.
Fulltext Systematic Review and Meta-Analysis of COVID-19 Vaccination Acceptance

Norhayati MN, Che Yusof R, Azman YM

Front Med (Lausanne), 2021;8:783982.
PMID: 35155467 DOI: 10.3389/fmed.2021.783982

INTRODUCTION: Vaccination is an essential intervention to curb the coronavirus disease 2019 (COVID-19) pandemic. This review aimed to estimate the pooled proportion of COVID-19 vaccine acceptance worldwide.
METHODS: A systematic search of the MEDLINE (PubMed) database using "COVID-19," "vaccine" and "acceptance" to obtain original research articles published between 2020 and July 2021. Only studies with full text and that were published in English were included. The Joanna Briggs Institute meta-analysis was used to assess the data quality. The meta-analysis was performed using generic inverse variance with a random-effects model using the Review Manager software.
RESULTS: A total of 172 studies across 50 countries worldwide were included. Subgroup analyses were performed with regard to vaccine acceptance, regions, population, gender, vaccine effectiveness, and survey time. The pooled proportion of COVID-19 vaccine acceptance was 61% (95% CI: 59, 64). It was higher in Southeast Asia, among healthcare workers, in males, for vaccines with 95% effectiveness, and during the first survey.
CONCLUSION: COVID-19 vaccine acceptance needs to be increased to achieve herd immunity to protect the population from the disease. It is crucial to enhance public awareness of COVID-19 vaccination and improve access to vaccines.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2021, identifier CRD42021268645.
Computational-aided design: minimal peptide sequence to block dengue virus transmission into cells

Arumugam AC, Agharbaoui FE, Khazali AS, Yusof R, Abd Rahman N, Ahmad Fuaad AAH

J Biomol Struct Dyn, 2020 Dec 31.
PMID: 33382015 DOI: 10.1080/07391102.2020.1866074

Dengue virus (DV) infection is one of the main public health concerns, affecting approximately 390 million people worldwide, as reported by the World Health Organization. Yet, there is no antiviral treatment for DV infection. Therefore, the development of potent and nontoxic anti-DV, as a complement for the existing treatment strategies, is urgently needed. Herein, we investigate a series of small peptides inhibitors of DV antiviral activity targeting the entry process as the promising strategy to block DV infection. The peptides were designed based on our previously reported peptide sequence, DN58opt (TWWCFYFCRRHHPFWFFYRHN), to identify minimal effective inhibitory sequence through molecular docking and dynamics studies. The in silico designed peptides were synthesized using conventional Fmoc solid-phase peptide synthesis chemistry, purified by RP-HPLC and characterized using LCMS. Later, they were screened for their antiviral activity. One of the peptides, AC 001, was able to reduce about 40% of DV plaque formation. This observation correlates well with the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) analysis - AC 001 showed the most favorable binding affinity through 60 ns simulations. Pairwise residue decomposition analysis has revealed four key residues that contributed to the binding of these peptides into the DV2 E protein pocket. This work identifies the minimal peptide sequence required to inhibit DV replication and explains the behavior observed on an atomic level using computational study.Communicated by Ramaswamy H. Sarma.
Averrhoa bilimbi pectin-based edible films: Effects of the linearity and branching of the pectin on the physicochemical, mechanical, and barrier properties of the films

Shafie MH, Yusof R, Samsudin D, Gan CY

Int J Biol Macromol, 2020 Nov 15;163:1276-1282.
PMID: 32673725 DOI: 10.1016/j.ijbiomac.2020.07.109

The potential of Averrhoa bilimbi pectin (ABP) as a source of biopolymer for edible film (EF) production was explored, and deep eutectic solvent (DES) (1% w/w) containing choline chloride-citric acid monohydrate at a molar ratio of 1:1 was used as the plasticizer. The EF-ABP3:1, which was produced from ABP with large branch size, showed a higher value of melting temperature (175.30 °C), tensile stress (7.32 MPa) and modulus (33.64 MPa). The EF-ABP3:1 also showed better barrier properties by obtaining the lowest water vapor transmission rates (1.10-1.18 mg/m2.s) and moisture absorption values (2.61-32.13%) depending on the relative humidity compared to other EF-ABPs (1.39-1.83 mg/m2.s and 3.48-51.50%, respectively) that have linear structure with smaller branch size. From these results, it was suggested that the galacturonic acid content, molecular weight, degree of esterification and pectin structure of ABP significantly influenced the properties of EFs. The interaction of highly branched pectin chains was stronger than the linear chains, thus reduced the effect of plasticizer and produced a mechanically stronger EF with better barrier properties. Hence, it was suggested that these EFs could be used as alternative degradable packaging/coating materials.
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.
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.
Fulltext Endoplasmic reticulum: a focal point of Zika virus infection

Mohd Ropidi MI, Khazali AS, Nor Rashid N, Yusof R

J Biomed Sci, 2020 Jan 20;27(1):27.
PMID: 31959174 DOI: 10.1186/s12929-020-0618-6

Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an arbovirus that can cause congenital abnormalities and is sexually transmissible. A series of outbreaks accompanied by unexpected severe clinical complications have captured medical attention to further characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. Endoplasmic reticulum (ER) and ER-related proteins are essential in ZIKV genome replication. This review highlights the subcellular localization of ZIKV to the ER and ZIKV modulation on the architecture of the ER. This review also discusses ZIKV interaction with ER proteins such as signal peptidase complex subunit 1 (SPCS1), ER membrane complex (EMC) subunits, and ER translocon for viral replication. Furthermore, the review covers several important resulting effects of ZIKV infection to the ER and cellular processes including ER stress, reticulophagy, and paraptosis-like death. Pharmacological targeting of ZIKV-affected ER-resident proteins and ER-associated components demonstrate promising signs of combating ZIKV infection and rescuing host organisms from severe neurologic sequelae.
Discovery of Dengue Virus Inhibitors

Abdullah AA, Lee YK, Chin SP, Lim SK, Lee VS, Othman R, et al.

Curr Med Chem, 2020;27(30):4945-5036.
PMID: 30514185 DOI: 10.2174/0929867326666181204155336

To date, there is still no approved anti-dengue agent to treat dengue infection in the market. Although the only licensed dengue vaccine, Dengvaxia is available, its protective efficacy against serotypes 1 and 2 of dengue virus was reported to be lower than serotypes 3 and 4. Moreover, according to WHO, the risk of being hospitalized and having severe dengue increased in seronegative individuals after they received Dengvaxia vaccination. Nevertheless, various studies had been carried out in search of dengue virus inhibitors. These studies focused on the structural (C, prM, E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) of dengue virus as well as host factors as drug targets. Hence, this article provides an overall up-to-date review of the discovery of dengue virus inhibitors that are only targeting the structural and non-structural viral proteins as drug targets.
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.
Psychometric properties of the Malay version of motivation scales in drug treatment

Shukri M, Min RM, Abdullah SS, Yusof RAM, Husain Z

Med J Malaysia, 2019 Oct;74(5):377-384.
PMID: 31649212

INTRODUCTION: In recognition of the role of motivation in drug use treatment, patient motivational screening instruments are needed for strategic planning and treatment. The aims of this study were to evaluate the reliability and validity of the Malay version of the Treatment Motivation Scale, and to compare the motivational levels of patients receiving substance abuse treatment with different modalities (inpatient vs. outpatient). The motivational scale consists of three scales: problem recognition, desire for help and treatment readiness.
METHOD: A convenience sample of 102 patients was recruited from four Cure and Care Service Centres in Malaysia.
RESULTS: Principal component analysis with varimax rotation supported two-factor solutions for each subscale: problem recognition, desire for help and treatment readiness, which accounted for 63.5%, 62.7% and 49.1% of the variances, respectively. The Cronbach's alpha coefficients were acceptable for the overall measures (24 items: ∝ = 0.89), the problem recognition scale (10 items; ∝ = 0.89), desire for help (6 items; ∝ = 0.64) and treatment readiness scale (8 items; ∝ = 0.60). The results also indicated significant motivational differences for different modalities, with inpatients having significantly higher motivational scores in each scale compared to outpatients.
CONCLUSION: The present study pointed towards the favourable psychometric properties of a motivation for treatment scale, which can be a useful instrument for clinical applications of drug use changes and treatment.
Carnosine exhibits significant antiviral activity against Dengue and Zika virus

Rothan HA, Abdulrahman AY, Khazali AS, Nor Rashid N, Chong TT, Yusof R

J. Pept. Sci., 2019 Aug;25(8):e3196.
PMID: 31290226 DOI: 10.1002/psc.3196

Dengue virus (DENV) and Zika virus (ZIKV) are flaviviruses transmitted to humans by their common vector, Aedes mosquitoes. DENV infection represents one of the most widely spread mosquito-borne diseases whereas ZIKV infection occasionally re-emerged in the past causing outbreaks. Although there have been considerable advances in understanding the pathophysiology of these viruses, no effective vaccines or antiviral drugs are currently available. In this study, we evaluated the antiviral activity of carnosine, an endogenous dipeptide (β-alanyl-l-histidine), against DENV serotype 2 (DENV2) and ZIKV infection in human liver cells (Huh7). Computational studies were performed to predict the potential interactions between carnosine and viral proteins. Biochemical and cell-based assays were performed to validate the computational results. Mode-of-inhibition, plaque reduction, and immunostaining assays were performed to determine the antiviral activity of carnosine. Exogenous carnosine showed minimal cytotoxicity in Huh7 cells and rescued the viability of infected cells with EC50 values of 52.3 and 59.5 μM for DENV2 and ZIKV infection, respectively. Based on the mode-of-inhibition assays, carnosine inhibited DENV2 mainly by inhibiting viral genome replication and interfering with virus entry. Carnosine antiviral activity was verified with immunostaining assay where carnosine treatment diminished viral fluorescence signal. In conclusion, carnosine exhibited significant inhibitory effects against DENV2 and ZIKV replication in human liver cells and could be utilized as a lead peptide for the development of effective and safe antiviral agents against DENV and ZIKV.

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