scholarly journals Structure-Based Design of Antivirals against Envelope Glycoprotein of Dengue Virus

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 367
Author(s):  
Mohd Ishtiaq Anasir ◽  
Babu Ramanathan ◽  
Chit Laa Poh
Keyword(s):  
Drug Discovery ◽  
Dengue Virus ◽  
Structural Information ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Denv Infection ◽  
Antiviral Drugs ◽  
Global Public Health ◽  
Viral Attachment ◽  
E Protein

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.

scholarly journals Doratoxylon apetalum, an Indigenous Medicinal Plant from Mascarene Islands, Is a Potent Inhibitor of Zika and Dengue Virus Infection in Human Cells

2019 ◽  
Vol 20 (10) ◽  
pp. 2382 ◽  
Author(s):  
Juliano G. Haddad ◽  
Andrea Cristine Koishi ◽  
Arnaud Gaudry ◽  
Claudia Nunes Duarte dos Santos ◽  
Wildriss Viranaicken ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Medicinal Plant ◽  
Dengue Virus ◽  
Denv Infection ◽  
Antiviral Drugs ◽  
Human Cells ◽  
Host Cells ◽  
Global Public Health ◽  
Denv Serotypes ◽  
Mascarene Islands

Zika virus (ZIKV) and Dengue virus (DENV) are mosquito-borne viruses of the Flavivirus genus that could cause congenital microcephaly and hemorrhage, respectively, in humans, and thus present a risk to global public health. A preventive vaccine against ZIKV remains unavailable, and no specific antiviral drugs against ZIKV and DENV are licensed. Medicinal plants may be a source of natural antiviral drugs which mostly target viral entry. In this study, we evaluate the antiviral activity of Doratoxylum apetalum, an indigenous medicinal plant from the Mascarene Islands, against ZIKV and DENV infection. Our data indicated that D. apetalum exhibited potent antiviral activity against a contemporary epidemic strain of ZIKV and clinical isolates of four DENV serotypes at non-cytotoxic concentrations in human cells. Time-of-drug-addition assays revealed that D. apetalum extract acts on ZIKV entry by preventing the internalisation of virus particles into the host cells. Our data suggest that D. apetalum-mediated ZIKV inhibition relates to virus particle inactivation. We suggest that D. apetalum could be a promising natural source for the development of potential antivirals against medically important flaviviruses.

scholarly journals Identification of the phytobioactive Polygonum cuspidatum as an antiviral source for restricting dengue virus entry

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yu-Ting Kuo ◽  
Ching-Hsuan Liu ◽  
Jin-Wei Li ◽  
Chien-Ju Lin ◽  
Alagie Jassey ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Antiviral Agents ◽  
Cell Types ◽  
Antiviral Effect ◽  
Denv Infection ◽  
Polygonum Cuspidatum ◽  
Tropical Regions ◽  
Viral Attachment ◽  
Excellent Starting Point ◽  
Starting Point

Abstract Dengue virus (DENV) is a mosquito-borne pathogen that is becoming a serious global threat, owing to its rising incidence in inter-tropical regions that yield over 50 million annual infections. There are currently no approved antiviral agents for the management of dengue, and recent shortcomings in its immunization called for immediate action to develop effective drugs with prophylactic ability to better manage its infection. In an attempt to discover novel antiviral sources, we identified the medicinal herb Polygonum cuspidatum (PC) as a bioactive botanical material against DENV infectivity. Specifically, the methanolic extract from PC rhizomes (PCME) potently inhibited DENV infection without causing significant cytotoxicity. Further examination on the viral life cycle demonstrated that PCME particularly targeted the initial stages of DENV infection, while pre- and post-infection treatments had no effect. More importantly, the PCME could efficiently inactivate DENV free virus particles and block the viral attachment and entry/fusion events without apparently influencing viral replication, egress, and cell-to-cell spread. The antiviral effect of PCME was also recapitulated in infection analysis using DENV pseudoparticles displaying viral structural proteins that mediate DENV particle entry. Besides, PCME treatment also inhibited direct DENV entry into several cell types relevant to its infection and reduced viral infectivity of other members of the Flaviviridae family, including the hepatitis C virus (HCV) and Zika virus (ZIKV). Due to its potency against DENV entry, we suggest that the phytobioactive extract from PC is an excellent starting point as an antiviral source material for further development of therapeutic strategies in the prophylactic management of DENV infection.

scholarly journals Antiviral activity of silymarin and baicalein against dengue virus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhao Xuan Low ◽  
Brian Ming OuYong ◽  
Pouya Hassandarvish ◽  
Chit Laa Poh ◽  
Babu Ramanathan
Keyword(s):  
Antiviral Activity ◽  
Dengue Virus ◽  
Viral Entry ◽  
Dengue Infection ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Vero Cells ◽  
Viral Envelope ◽  
E Protein

AbstractDengue is an arthropod-borne viral disease that has become endemic and a global threat in many countries with no effective antiviral drug available currently. This study showed that flavonoids: silymarin and baicalein could inhibit the dengue virus in vitro and were well tolerated in Vero cells with a half-maximum cytotoxic concentration (CC50) of 749.70 µg/mL and 271.03 µg/mL, respectively. Silymarin and baicalein exerted virucidal effects against DENV-3, with a selective index (SI) of 10.87 and 21.34, respectively. Baicalein showed a better inhibition of intracellular DENV-3 progeny with a SI of 7.82 compared to silymarin. Baicalein effectively blocked DENV-3 attachment (95.59%) to the Vero cells, while silymarin prevented the viral entry (72.46%) into the cells, thus reducing viral infectivity. Both flavonoids showed promising antiviral activity against all four dengue serotypes. The in silico molecular docking showed that silymarin could bind to the viral envelope (E) protein with a binding affinity of − 8.5 kcal/mol and form hydrogen bonds with the amino acids GLN120, TRP229, ASN89, and THR223 of the E protein. Overall, this study showed that silymarin and baicalein exhibited potential anti-DENV activity and could serve as promising antiviral agents for further development against dengue infection.

scholarly journals Target Identification Using Homopharma and Network-Based Methods for Predicting Compounds Against Dengue Virus-Infected Cells

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1883 ◽  
Author(s):  
Kowit Hengphasatporn ◽  
Kitiporn Plaimas ◽  
Apichat Suratanee ◽  
Peemapat Wongsriphisant ◽  
Jinn-Moon Yang ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Target Identification ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Target Prediction ◽  
Denv Infection ◽  
Inhibitory Effect ◽  
Active Compounds ◽  
Phenolic Lipids ◽  
Human Proteins

Drug target prediction is an important method for drug discovery and design, can disclose the potential inhibitory effect of active compounds, and is particularly relevant to many diseases that have the potential to kill, such as dengue, but lack any healing agent. An antiviral drug is urgently required for dengue treatment. Some potential antiviral agents are still in the process of drug discovery, but the development of more effective active molecules is in critical demand. Herein, we aimed to provide an efficient technique for target prediction using homopharma and network-based methods, which is reliable and expeditious to hunt for the possible human targets of three phenolic lipids (anarcardic acid, cardol, and cardanol) related to dengue viral (DENV) infection as a case study. Using several databases, the similarity search and network-based analyses were applied on the three phenolic lipids resulting in the identification of seven possible targets as follows. Based on protein annotation, three phenolic lipids may interrupt or disturb the human proteins, namely KAT5, GAPDH, ACTB, and HSP90AA1, whose biological functions have been previously reported to be involved with viruses in the family Flaviviridae. In addition, these phenolic lipids might inhibit the mechanism of the viral proteins: NS3, NS5, and E proteins. The DENV and human proteins obtained from this study could be potential targets for further molecular optimization on compounds with a phenolic lipid core structure in anti-dengue drug discovery. As such, this pipeline could be a valuable tool to identify possible targets of active compounds.

scholarly journals Potential Phosphorylation of Viral Nonstructural Protein 1 in Dengue Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1393
Author(s):  
Thanyaporn Dechtawewat ◽  
Sittiruk Roytrakul ◽  
Yodying Yingchutrakul ◽  
Sawanya Charoenlappanit ◽  
Bunpote Siridechadilok ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nonstructural Protein ◽  
Antiviral Drug ◽  
Denv Infection ◽  
Site Directed Mutagenesis ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Multifunctional Protein ◽  
Nonstructural Protein 1 ◽  
Underlying Mechanisms

Dengue virus (DENV) infection causes a spectrum of dengue diseases that have unclear underlying mechanisms. Nonstructural protein 1 (NS1) is a multifunctional protein of DENV that is involved in DENV infection and dengue pathogenesis. This study investigated the potential post-translational modification of DENV NS1 by phosphorylation following DENV infection. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), 24 potential phosphorylation sites were identified in both cell-associated and extracellular NS1 proteins from three different cell lines infected with DENV. Cell-free kinase assays also demonstrated kinase activity in purified preparations of DENV NS1 proteins. Further studies were conducted to determine the roles of specific phosphorylation sites on NS1 proteins by site-directed mutagenesis with alanine substitution. The T27A and Y32A mutations had a deleterious effect on DENV infectivity. The T29A, T230A, and S233A mutations significantly decreased the production of infectious DENV but did not affect relative levels of intracellular DENV NS1 expression or NS1 secretion. Only the T230A mutation led to a significant reduction of detectable DENV NS1 dimers in virus-infected cells; however, none of the mutations interfered with DENV NS1 oligomeric formation. These findings highlight the importance of DENV NS1 phosphorylation that may pave the way for future target-specific antiviral drug design.

scholarly journals Indole – a promising pharmacophore in recent antiviral drug discovery

2020 ◽  
Vol 11 (12) ◽  
pp. 1335-1353
Author(s):  
Atukuri Dorababu
Keyword(s):  
Drug Discovery ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Indole Derivatives ◽  
Sar Studies

The antiviral properties of indole derivatives discovered recently are described considering their inhibitory values, cytotoxicity and SAR studies. The study helps researchers to carry out further investigation and to design efficient antiviral agents.

scholarly journals Antiviral Efficacy of the Anesthetic Propofol against Dengue Virus Infection and Cellular Inflammation

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Ting-Jing Shen ◽  
Chia-Ling Chen ◽  
Ming-Kai Jhan ◽  
Po-Chun Tseng ◽  
Rahmat Dani Satria ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Cell Model ◽  
Antiviral Agents ◽  
Denv Infection ◽  
Severe Dengue ◽  
Cellular Inflammation ◽  
Antiviral Effects ◽  
Endosomal Acidification ◽  
Adults And Children

Propofol, 2,6-diisopropylphenol, is a short-acting intravenous sedative agent used in adults and children. Current studies show its various antimicrobial as well as anti-inflammatory effects. Dengue virus (DENV) is an emerging infectious pathogen transmitted by mosquitoes that causes mild dengue fever and progressive severe dengue diseases. In the absence of safe vaccines and antiviral agents, adjuvant treatments and supportive care are generally administered. This study investigated the antiviral effects of propofol against DENV infection and cellular inflammation by using an in vitro cell model. Treatment with propofol significantly inhibited DENV release 24 h postinfection in BHK-21 cells. Furthermore, it also blocked viral protein expression independent of the translational blockade. Propofol neither caused inhibitory effects on endosomal acidification nor prevented dsRNA replication. Either the proinflammatory TNF-α or the antiviral STAT1 signaling was reduced by propofol treatment. These results provide evidence to show the potential antiviral effects of the sedative propofol against DENV infection and cellular inflammation.

scholarly journals Broad-spectrum virucidal activity of bacterial secreted lipases against flaviviruses, SARS-CoV-2 and other enveloped viruses

2020 ◽  
Author(s):  
Xi Yu ◽  
Liming Zhang ◽  
Liangqin Tong ◽  
Nana Zhang ◽  
Han Wang ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Lipase Activity ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Viral Envelope ◽  
Global Public Health ◽  
Virucidal Activity ◽  
Extracellular Milieu

AbstractViruses are the major aetiological agents of acute and chronic severe human diseases that place a tremendous burden on global public health and economy; however, for most viruses, effective prophylactics and therapeutics are lacking, in particular, broad-spectrum antiviral agents. Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation of CbAE-1 in its lipase motif fully abrogated the virucidal ability. Furthermore, CbAE-2 presented low toxicity in vivo and in vitro, highlighting its potential as a broad-spectrum antiviral drug.

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