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Flavonoids: promising natural compounds against viral infections

Zakaryan H, Arabyan E, Oo A, Zandi K

Arch Virol, 2017 Sep;162(9):2539-2551.
PMID: 28547385 DOI: 10.1007/s00705-017-3417-y

Flavonoids are widely distributed as secondary metabolites produced by plants and play important roles in plant physiology, having a variety of potential biological benefits such as antioxidant, anti-inflammatory, anticancer, antibacterial, antifungal and antiviral activity. Different flavonoids have been investigated for their potential antiviral activities and several of them exhibited significant antiviral properties in in vitro and even in vivo studies. This review summarizes the evidence for antiviral activity of different flavonoids, highlighting, where investigated, the cellular and molecular mechanisms of action on viruses. We also present future perspectives on therapeutic applications of flavonoids against viral infections.
End-stage kidney disease in Brunei Darussalam (2011-2020)

Johan NH, Oo AP, Pisharam JK, Rosalina S, Koh D, Tan J

Med J Malaysia, 2023 Jan;78(1):54-60.
PMID: 36715192

INTRODUCTION: The Brunei Dialysis and Transplant Registry (BDTR) recorded data on patients with end-stage kidney disease (ESKD) from 2011 to 2020, mainly for planning of services and benchmarking of standards. We report the trends of epidemiologic and performance parameters, compare performances between modalities of Kidney Replacement Therapy and evaluate the survival of ESKD patients over the 10-year period.
MATERIALS AND METHODS: Three groups of data were analysed from the BDTR over the 10-year period. Epidemiological data, blood parameters and dialysis are key performance indicators.
RESULTS: There are increments in prevalence and incidence of treated ESKD patients in Brunei over 10 years, especially with haemodialysis (HD). The projected prevalence and incidence showed an anticipated annual increase of 42.2 per million population (pmp) and 9.9 pmp respectively. Diabetes mellitus (DM) (79%) was the main cause of ESKD. HD (86%), peritoneal dialysis (PD) (9%) and transplant (5%) were the main modalities of kidney replacement therapy in 2020. Cumulative results over the decade showed significant improvements in serum phosphate, peritonitis rates and HD blood flow rates. PD patients have better survival rates, lower systolic blood pressure and better adequacy. PD survival (patient survival of 91%, 73% and 56% at 1, 3 and 5 years respectively) was superior to HD survival (86% and 64% at 1 and 2 years, respectively), but patient demographics (age and DM status) were different. The 2020 dataset showed satisfactory anaemia management but mineral bone disease management was sub-optimal. Seventy percent of prevalent HD patients had arteriovenous fistula access. Thirty-two percent and fifty-two percent of HD and PD patients, respectively, achieved target dialysis adequacy. Peritonitis rate was 0.3 episodes per patient year.
CONCLUSION: Brunei has a high incidence and prevalence of treated ESKD in the last decade, especially DM-related ESKD. This study has identified many specific areas to be targeted for improvements and provided evidence for further proliferation of PD and transplant preference policy.
Exploring the in vitro potential of celecoxib derivative AR-12 as an effective antiviral compound against four dengue virus serotypes

Hassandarvish P, Oo A, Jokar A, Zukiwski A, Proniuk S, Abu Bakar S, et al.

J Antimicrob Chemother, 2017 09 01;72(9):2438-2442.
PMID: 28666323 DOI: 10.1093/jac/dkx191

Objectives: With no clinically effective antiviral options available, infections and fatalities associated with dengue virus (DENV) have reached an alarming level worldwide. We have designed this study to evaluate the efficacy of the celecoxib derivative AR-12 against the in vitro replication of all four DENV serotypes.
Methods: Each 24-well plate of Vero cells infected with all four DENV serotypes, singly, was subjected to treatments with various doses of AR-12. Following 48 h of incubation, inhibitory efficacies of AR-12 against the different DENV serotypes were evaluated by conducting a virus yield reduction assay whereby DENV RNA copy numbers present in the collected supernatant were quantified using qRT-PCR. The underlying mechanism(s) possibly involved in the compound's inhibitory activities were then investigated by performing molecular docking on several potential target human and DENV protein domains.
Results: The qRT-PCR data demonstrated that DENV-3 was most potently inhibited by AR-12, followed by DENV-1, DENV-2 and DENV-4. Our molecular docking findings suggested that AR-12 possibly exerted its inhibitory effects by interfering with the chaperone activities of heat shock proteins.
Conclusions: These results serve as vital information for the design of future studies involving in vitro mechanistic studies and animal models, aiming to decipher the potential of AR-12 as a potential therapeutic option for DENV infection.
Baicalein and baicalin as Zika virus inhibitors

Oo A, Teoh BT, Sam SS, Bakar SA, Zandi K

Arch Virol, 2019 Feb;164(2):585-593.
PMID: 30392049 DOI: 10.1007/s00705-018-4083-4

At present, there is no effective antiviral agent for Zika virus (ZIKV), an arbovirus that is known for its teratogenic effects on newborns. Baicalein and baicalin were found to be capable of downregulating ZIKV replication up to 10 hours postinfection, while prophylactic effects were evident in pre-treated cells. Baicalein exhibited its highest potency during intracellular ZIKV replication, whereas baicalin was most effective against virus entry. Our in silico interaction assays predicted that both compounds exhibited the strongest binding affinities towards ZIKV NS5, while the virus envelope glycoprotein was the least likely target protein. These findings serve as a crucial platform for further in-depth studies to decipher the underlying anti-ZIKV mechanism(s) of each compound.
Deciphering the potential of baicalin as an antiviral agent for Chikungunya virus infection

Oo A, Rausalu K, Merits A, Higgs S, Vanlandingham D, Bakar SA, et al.

Antiviral Res, 2018 02;150:101-111.
PMID: 29269135 DOI: 10.1016/j.antiviral.2017.12.012

The past decade has seen the re-emergence of Chikungunya virus (CHIKV) as a major global health threat, affecting millions around the world. Although fatal infections are rare among infected patients, the occurrence of long-lasting polyarthralgia has a significant impact on patients' quality of lives and ability to work. These issues were the stimuli for this study to determine the potential of baicalin, a bioflavonoid, as the novel antiviral compound against CHIKV. It was found that baicalin was well tolerated by Vero, BHK-21 and HEK 293T cells with maximal nontoxic doses >600 μM, ≈ 350 μM and ≈110 μM, respectively. Antiviral assays indicated that baicalin was the most effective inhibitor when tested for its direct virucidal activity with EC50 ≈ 7 μM, followed by inhibition of virus entry into the host cell, attachment of virus particle to cellular receptors and finally intracellular replication of viral RNA genome. In silico analysis using molecular docking demonstrated close interactions between baicalin and CHIKV envelope protein with considerably strong binding affinity of -9.7 kcal/mol. qRT-PCR analysis revealed that baicalin had the greatest effect on the synthesis of viral negative stand RNA with EC50 ≈ 0.4 μM followed by the inhibition of synthesis of positive-strand genomic (EC50 ≈ 13 μM) and subgenomic RNAs (EC50 ≈ 14 μM). These readings indicate that the compound efficiently inhibits replicase complexes formation but is a less potent inhibitor of existing replicase complexes. Coherent with this hypothesis, the use of recombinant CHIKV replicons harboring Renilla luciferase marker showed that replication of corresponding replicon RNAs was only slightly downregulated at higher doses of baicalin, with EC50 > 100 μM. Immunofluorescence and western blotting experiments demonstrated dose-dependent inhibition of expression of different viral proteins. It was also observed that levels of important protein markers for cellular autophagy (LC3) and apoptosis (Bax) were reduced in baicalin treatment groups as compared with untreated virus infected controls. In summary, given its low toxicity and high efficacy against CHIKV, baicalin has great potential to be developed as the novel antiviral compound for CHIKV. In vivo studies to evaluate its activity in a more complexed system represent a necessary step for future analysis.
Fulltext Computational Approach Towards Exploring Potential Anti-Chikungunya Activity of Selected Flavonoids

Seyedi SS, Shukri M, Hassandarvish P, Oo A, Shankar EM, Abubakar S, et al.

Sci Rep, 2016 Apr 13;6:24027.
PMID: 27071308 DOI: 10.1038/srep24027

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes chikungunya infection in humans. Despite the widespread distribution of CHIKV, no antiviral medication or vaccine is available against this virus. Therefore, it is crucial to find an effective compound to combat CHIKV. We aimed to predict the possible interactions between non-structural protein 3 (nsP) of CHIKV as one of the most important viral elements in CHIKV intracellular replication and 3 potential flavonoids using a computational approach. The 3-dimensional structure of nsP3 was retrieved from the Protein Data Bank, prepared and, using AutoDock Vina, docked with baicalin, naringenin and quercetagetin as ligands. The first-rated ligand with the strongest binding affinity towards the targeted protein was determined based on the minimum binding energy. Further analysis was conducted to identify both the active site of the protein that reacts with the tested ligands and all of the existing intermolecular bonds. Compared to the other ligands, baicalin was identified as the most potential inhibitor of viral activity by showing the best binding affinity (-9.8 kcal/mol). Baicalin can be considered a good candidate for further evaluation as a potentially efficient antiviral against CHIKV.
Fulltext Baicalein and Baicalin Inhibit SARS-CoV-2 RNA-Dependent-RNA Polymerase

Zandi K, Musall K, Oo A, Cao D, Liang B, Hassandarvish P, et al.

Microorganisms, 2021 Apr 22;9(5).
PMID: 33921971 DOI: 10.3390/microorganisms9050893

Coronavirus Disease 2019 (COVID-19) is a deadly emerging infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Because SARS-CoV-2 is easily transmitted through the air and has a relatively long incubation time, COVID-19 has rapidly developed into a global pandemic. As there are no antiviral agents for the prevention and treatment of this severe pathogen except for remdesivir, development of antiviral therapies to treat infected individuals remains highly urgent. Here, we showed that baicalein and baicalin exhibited significant antiviral activity against SARS-CoV-2, the causative agent of COVID-19 through in vitro studies. Our data through cell-based and biochemical studies showed that both compounds act as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors directly and inhibit the activity of the SARS-CoV-2 RdRp, but baicalein was more potent. We also showed specific binding of baicalein to the SARS-CoV-2 RdRp, making it a potential candidate for further studies towards therapeutic development for COVID-19 as a selective non-nucleoside polymerase inhibitor.