INTRODUCTION:

DENGUE:

Dengue Fever is also known as break bone fever is an infectious tropical disease caused by the dengue virus. It’s transmitted by several species of mosquito. This fever is observed Frequently in people who travel around the world.

It caused by any of the four dengue virus serotypes: DENVs 1–4. It is a mosquito-borne disease and is primarily transmitted to humans by the female Aedes mosquito. The disease is mainly concentrated in tropical and subtropical regions, putting nearly a third of the human population, Worldwide, at risk of the infection. Infection with DENV results in varying degrees of patholological conditions, ranging from mild asymptomatic dengue fever [DF] to severe dengue hemorrhage fever [DHF] and dengue shock syndrome [DSS] which may turn fetal.

Millions of dengue cases occur worldwide each year. Most recently, an outbreak occurred in Texas. Though usually a nonspecific febrile illness that resolves with supportive therapy, the clinical spectrum ranges from asymptomatic to severe hemorrhage and sudden fatal shock. The potential exists for the introduction of dengue virus into other parts of the United States, and for secondary transmission in areas with vector mosquitoes, because of increased travel to and from regions of the Americas where dengue is endemic.

Figure No 1. Dengue Virus

Dengue fever is the fastest emerging arboviral infection spore. Dengue has the most important arboviral infection world with more than 30 million. Dengue fever estimated to occur each year. The dengue virus is the cause of dengue fever. Dengue viruses are the causative agent of a dengue fever. Its genome is about 11000 bases that the codes for three structural proteins (Membrane protein M, capsid protein C, and envelop protein E) and seven nonstructural proteins it is also including the short non-coding reign on both the 5 and 3 ends. The dengue virus genome is 11644 nucleotides in length, and is composed of three structural protein genes encoding the core protein (C),), envelope protein (E), a membrane associated protein (M), and seven nonstructural protein (NS) genes. Non-structural proteins is enveloped by glycoprotein, NS1 is of diagnostic and pathological Importancs.

Figure No 2. Structure of dengue virus

Literature and Review⁵:

1) In the 18th century, dengue has caused repeated epidemics worldwide H. Graham in 1903 implicated Aedes aegypti as the vector for the disease and the virus was isolated in 1944 by Albert Sabin et al.

2) Drs. Hanh and Quy were asked to review published frameworks for assessing project sustainability, using the Ovid Medline database to search for relevant articles, and also to follow up references in the articles identified.

3) From articles retrieved, an initial framework applicable to CBDC projects was considered more specifically in relation to the 1998–2000 community-based dengue control program in Nam Dinh province, because this was thought to provide the most stringent test.

4) We tested the framework against a project commune that was part of community-based dengue vector control activities from 1998 to 2000: Xuan Phong in Xuan Truong District of Nam Dinh Province, Vietnam(20°16’ N, 106°20’ E).

VACCINATION⁶:

The first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was first registered in Mexico in December, 2015. CYD-TDV is a live recombinant tetravalent dengue vaccine that has been evaluated as a 3-dose series on a 0/6/12-month schedule in Phase III clinical studies. It has been registered for use in individuals 9-45 years of age living in endemic areas.

Dengue fever:

Dengue (DENG-gey) fever is a mosquito-borne illness that occurs in tropical and subtropical areas of the world. Mild dengue fever causes a high fever and flu-like symptoms. The severe form of dengue fever, also called dengue hemorrhagic fever, can cause serious bleeding, a sudden drop in blood pressure (shock) and death.

CAUSE⁷:

Dengue is caused due to four viruses, namely - DENV-1, DENV-2, DENV-3, and DENV-4. The virus enters a mosquito when it bites an already infected person. And the illness is spread when it bites a healthy person, and the virus spreads through the person’s bloodstream.

SYMPTOMS⁷:

· Sudden, high fever-

· Severe headaches and pain behind the eyes-

· Nausea and Vomiting-

· Skin rashes-

· Low platelet count-

· Swollen lymph nodes-

· Severe joint, muscle and abdominal pain-

SPEAD⁽⁸⁾ :

A vector is a vehicle that carries and transmits a disease to its host organism. Vectors include animals and microorganisms that transmit different diseases.

The virus is most typically UN fold to somebody's through the bite of associate infected dipteron. Infectious disease virus could also be passed from a mother to her unhatched baby. The most transmission is thru mosquitoes that typically acquire the virus whereas feeding on the blood of the associate infected person. Once virus incubation for eight to 10 days, associate infected dipteron is capable, throughout inquiring and blood feeding, of transmitting the virus for the remainder of its life. There are no thanks to telling if a dipteron is carrying the infectious disease virus.

TRANSMISSION:

Figure 3. Transmission of Dengue

Life Cycle of dengue mosquito⁹:

Aedes aegypti is a so-called holometabolous insect. This means that the insects goes through a complete metamorphosis with an egg, larvae, pupae, and adult stage. The adult life span can range from two weeks to a month depending on environmental conditions. The life cycle of Aedes aegypti can be completed within one-and-a-half to three weeks.

Figure No 4. Life cycle of mosquito

Life stages of Aedes aegypti mosquito:

· EGG-

· LARVEA-

· PUPA-

· ADULT-

Methods of bioanalysis for anti-dengue activity^4,10,,15:

1. Pre clinical-

2. Clinical-

3. RT-PCR for detection of Dengue viruses in clinical samples¹⁰:

Figure 5. Methods for bioanalysis of antidengue activity

TREATMENT^4,11:

Agents in development for anti-dengue activity:

Direct acting antivirals:

Nucleoside analogues:

Balapiravir:

A prodrug of the nucleoside analogue 4′-azidocytidine is a potent inhibitor of the in vitro replication of the hepatitis C virus (HCV). Once the parent compound has been delivered in the host cell and has been phosphorylated to its 5′-triphosphate metabolite, it acts as an inhibitor of the viral RdRp. An oral form, R-1626 (balapiravir), is rapidly converted to the active compound R-1479 and was found to suppress HCV infection in vitro and in vivo.

RNA dependent RNA polymerase (NS5) inhibitors:

N-sulfonylanthranilic acid derivatives were identified as DENV RdRp inhibitors through screening of one million compound. A novel class of compounds containing N-sulfonylanthranilic acid was found to specifically inhibit dengue viral polymerase. The structural requirements for inhibition and a preliminary structure-activity relationship are described. A UV cross-linking experiment was used to map the allosteric binding site of the compound on the viral polymerase.

Protease (NS2b-NS3) Inhibitors^12,13:

The viral nonstructural 2B and 3 (NS2B-NS3) protease complex is crucial for virus replication and hence, it is considered to be a good anti-viral target. Leaf extracts from Carica papaya is generally prescribed for patients with dengue fever, but there are no scientific evidences for its anti-dengue activity; hence we intended to investigate the anti-viral activity of compounds present in the leaves of Carica papaya against dengue 2 virus (DENV-2).

Quinoline containing compounds:

Using virtual screening for DENV protease inhibitors followed by scaffold hopping, to expand chemical diversity, then a DENV luciferase reporter replicon assay, Deng etal. have described 17 new compounds with NS2b-NS3 protease inhibitor activity, which can now serve as potential lead structures for further discovery efforts.

Methyl transferase (NS5) inhibitor¹⁴:

With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 Ado Met-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques.

Capsid inhibitor:

Capsid-targeted viral inactivation (CTVI) has emerged as a conceptually powerful antiviral strategy that exploits viral structural proteins to target a destructive enzyme specifically into progeny virions.

No clinically approved anti-DENV drug is currently available. Here we report the high-resolution co crystal structure (1.5 Å) of the DENV-2 capsid protein in complex with an inhibitor that potently suppresses DENV-2 but not other DENV serotypes.

Peptide inhibitors of various DENV protein:

Inhibition of DENV attachment and entry to host cells by blocking DENV envelope (E) protein is an attractive strategy for anti-DENV drug development. A hydrophobic pocket on the DENV E protein is essential for structural transition in the membrane fusion, and inhibition of this process is able to inhibit DENV infection.

Mycophenolic acid:

Cellular autophagy (Macrophagy) is a self-degradative process, executed through the network of autophagy associated genes (ATGs) encoded proteins. Both in vitro and in vivo studies suggest that dengue virus (DENV) induces autophagy and supports the viral genome replication and translation.

Agents that target host mediated post translational modifications⁴:

Α Glycosidase inhibitors:

Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II.

A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease.

Vitamin D:

Vitamin D has a well characterized role in calcium and phosphorus homeostasis, but additionally has a role in the immune response to bacterial and viral pathogens. In this study a number of fused bicyclic derivatives of 1H-pyrrolo[1,2]imidazol-1-one with vitamin D receptor (VDR) agonist activity were evaluated for possible anti-DENV activity. The results showed that five of the compounds were able to significantly inhibit DENV infection.

Heparin and Heparin Sulphate:

Suramin effectively prevented dengue virus infection of target cells, indicating that the envelope protein-target cell receptor interaction is a critical determinant of infectivity. The dengue envelope protein sequence includes two putative glycosaminoglycan-binding We found that the cellular receptor utilized by dengue envelope protein to bind to target cells is a highly sulfated type of heparan sulfate.

Viral sensor (RIG-I and TLR3) agonists:

A growing body of evidence has demonstrated the role of components of innate immunity, including Toll-like receptors (TLRs), the retinoic acid-inducible gene I/melanoma-differentiation factor 5 (RIG-I/MDA5) and microRNAs (miRNAs) in the recognition of dengue virus (DENV) or its components by infected cells. TLR3, TLR7/8 and RIG-I/MDA5 sense genomic RNA or dsRNA, the product of an intermediate step of DENV replication, activating intracellular pathways leading to the production of antiviral effectors, including interferon and pro-inflammatory cytokines.

Ivermectine:

Ivermectin is an FDA-approved broad spectrum anti-parasitic agent that in recent years we, along with other groups, have shown to have anti-viral activity against a broad range of viruses. The anti-helminthic drug ivermectin it has been identified as an inhibitor of the nuclear importer import in α/β. Because DENV NS5polymerase activity requires import in α/β, anti-viral properties of ivermectin were explored, and it is revealed that pre-treatment with ivermectin inhibited DENV infection of vero cells.

Chloroquine:

Chloroquine is an inexpensive, well-tolerated lysosomotropic 4-amino-quinoline derivative, which is well known as an anti-malarial drug but also possesses in vitro anti-viral activity, including anti-DENV activity, potentially related to its effect of increasing endosomal pH.

RNAi:

RNA interference (RNAi) is an important antiviral defense response in plants and invertebrates; however, evidences for its contribution to mammalian antiviral defense are few. In the present study, we demonstrate the anti-dengue virus role of RNAi in mammalian cells. We observed down regulation of many known human microRNAs (miRNAs) in response to viral infection.

Medicinal Plant:

medicinal plants are always important part of traditional remedy and treatment sources for various diseases in India as well as worldwide. The medicinal plants are famous to their bioactive compounds, which are the rich source of pharmaceuticals, some of which contains good antiviral activity. The WHO and Ayurveda suggested that the use of medicinal plant extracts and their derivatives is helpful to fight against dengue disease.

KNOWLEDGE GAINED:

1) This project helps to understand about Dengue Fever, Symptoms, Causes, Prevention, Diagnosis and Treatments.

2) The majority of respondents identified initial symptoms of Dengue Fever as having a fever for more than two days (85.5%) and having a headache and joint pains (55.5%).

3) Dengue is often a leading cause of illness in areas with risk. Each year, up to 400 million people get infected with dengue. Approximately 100 million people get sick from infection, and 22,000 die from severe dengue. Dengue is caused by one of any of four related viruses: Dengue virus 1, 2, 3, and 4.

4) An emerging therapy for dengue this project helps to understand Molecular tests for dengue virus (PCR)—detect the presence of the virus itself; these tests can diagnose dengue fever up to 7 days after the onset of symptoms and can be used to determine which of the 4 different serotypes of dengue virus is causing the infection.

5) In this dengue disease, A vaccine to prevent dengue (Dengvaxia®) is licensed and available in some countries for people aged 9 to 45 years. The World Health Organization recommends that the vaccine only be given to persons with confirmed previous dengue virus infection.

CONLUSION:

Here concluded that, A vaccine is not completely protective and vector control measures lack sustainable outcomes even organized area like Singapore approaches antiviral discovery.

Although no antiviral agents has yet been found to be effective against in acute dengue. While significant challenges still exist in the dengue research community in bringing a dengue compound through the entire process, we are optimistic that is enough momentum and effort in industry, governmental and charitable organizations for development.

Dengue fever is a mosquito born disease that occurs in tropical and subtropical areas of the world. Mild dengue fever causes a high fever and flu like symptoms. The government and pharmaceutical industries development for a new-strategies to improve the diagnosis and treatment of dengue. Dengue virus is a currently a problematic global infection.

The treatment of dengue antiviral drug is under investigation combined efforts of health care industries, governing bodies and efforts at individual level help to prevalence of dengue. Dengue fever is usually self-limiting disease. A Total view of outbreak of dengue fever in various states of India it become imperative for primary care physicians to have updated knowledge for diagnosis and management.

REFERENCES:

1. Tayade M.R, Shinkar D.M, Patil P.B, Saudagar R.B. International Journal of Current Pharmacuetical Research, doi.org/10.22159/ijcpr.2018v10i2.25848.

2. Cameron P Simmons, in Infectious Diseases (Third Edition), 2010.

3. María G. Guzman, Ana B. Perez, in International Encyclopedia of Public Health (Second Edition), 2017.

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5. https://www.researchgate.net/profile/Peter-Hill 4/publication/23974505_Development_of_a_Framework_for_Evaluating_the_Sustainability_of_Community based_Dengue_Control_Projects/links/0c960517f09774fa17000000/Development-of-a-Framework-for-Evaluating-the-Sustainability-of-Community-based-Dengue-Control-Projects.pdf

6. https://www.who.int/news-room/q-a-detail/dengue-vaccines

7. https://www.dettol.co.in/en/illness-prevention/illnesses/everything-you-need-to-know-about-dengue/?gclid=Cj0KCQjwub-HBhCyARIsAPctr7zwb_eGG2HXMom2Xcw4bpsV4NV4_ijV5D5MKFMM7B0gcdbfdi1d1mgaAtCxEALw_wcB&gclsrc=aw.ds

8. Dengue Virus Net. "Aedes aegypti." Dengue transmission by Aedes aegypti mosquito (2011).

9. https://www.cdc.gov/dengue/resources/factsheets/mosquitolifecyclefinal.pdf

10. Nazia Afreen, Irshad H. Naqvi, Shobha Broor, Anwar Ahmed, Shama Parveen, Phylogenetic and Molecular Clock Analysis of Dengue Serotype 1 and 3 from New Delhi, India 2015 doi.org/10.1371/journal.pone.0141628.

11. https://journals.asm.org/doi/full/10.1128/JVI.79.8.5116-5128.2005

12. https://journals.asm.org/doi/full/10.1128/JVI.79.8.5116-5128.2005

13. Research Article | Open Access Volume 2012 |Article ID 251482 | 16. https://www.who.int/news-room/q-a-detail/dengue-vaccines

14. https://www.who.int/news-room/q-a-detail/dengue-vaccines

Received on 27.08.2021 Modified on 07.11.2021

Asian J. Pharm. Res. 2022; 12(1):105-109.

DOI: 10.52711/2231-5691.2022.00016

An Emerging Therapy for Dengue

Snehal D. Kothavale, S.S. Suryawanshi, Sachinkumar V. Patil