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The global problem of Dengue
Dengue fever is a widespread global health issue, with more than 3.2 million reported cases as per 2015 statistics of WHO, however the un-reported cases, especially in middle income countries and rural areas may add to this number . One study estimates that approximately 390 million dengue infections occur per year (95% CI), with 96 million of these presenting clinically . Moreover, an estimated ~3 billion people that represents almost half of the world’s population are considered at risk for dengue infection. Recent estimates find that 128 countries worldwide are at risk for dengue infection, which includes 36 that had once been classified as dengue-free . Indian subcontinent and Asia pacific is more vulnerable due to climatic and other factors.
The Dengue virus
The discovery and identification of dengue virus was identified by Ren Kimura and Susumu Hotta in 1943 while studying, blood samples of patients during dengue epidemic in Nagasaki, Japan. A year later, Albert B. Sabin and Walter Schlesinger independently isolated the dengue virus which is now referred to as dengue virus 1 (DEN-1). Th e dengue viruses are members of the genus Flavivirus in the family Flaviviridae. There are four serotypes of DENV, namely DEN-1, DEN-2, DEN-3, and DEN-4. At genomic lev el, these four serotypes share approximately 65% of their genomes. Despite these variations, infection with each of the dengue serotypes results in the same disease and range of clinical symptoms.
Dengue virus proteins
The dengue virus genome is ssRNA, often referred to as positive-sense RNA as it can be directly translated into proteins . This viral genome contains ten genes which synthesize a single, long polypeptide which is later processed into ten proteins by means of proteolytic cleavage. Seven of these ten proteins are nonstructural protei ns: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. These nonstructural proteins play roles in viral replication and assembly, remaining three are structural proteins namely , capsid [C], membrane [M], and envelope [E] proteins. These proteins, including the genome assemble into a spherical assembly, containing nucleocapsid in the core, for from viral genome and C proteins. The nucleocapsid is surrounded by a viral envelope consisting of lipid bilayer formed from host cells. Protein E and M are embeded in the membrane and span through the lipid bilayer forming a protective outer layer that controls the entry of the virus into human cells . The nonstructural protein 1 (NS1) is a flexible conserved N-linked nonstructural glycoprotein (48?kDa) with six invariant intramolecular disulfide bonds that are expressed on the cell surface and secreted into the extracellular space, where it has immune evasion activities [6-7]. The NS2A protein of DENV is an important constituent of the viral replication complex that plays a vital role in the virion assembly and and antagonizes the host immune response . NS3 contains a serine protease domain and a RNA helicase domain which has nucleotide triphosphatase activities that are essential for RNA replication and viral assembly . NS4A and NS4B proteins are membrane-anchored proteins and essential for the formation of DENV replication complex [10-12]. NS5 protein of DENV is the biggest protein of 900 amino acid residues and reported as the most conserved protein in the genus flaviviruses. It contains two different domains; a methyltransferase (MTase) domain and a RNA dependent RNA polymerase (RdRp) domain. MTase domain caps the DENV RNA genome, a step required for its stability and translation into DENV polyproteins by host cell. The RdRp domain synthesizes the anti-genome and offspring genome [12-16].
DenvInD: Salient features
Considering the escalation of research driven by scientific concern for reducing the dengue burden, several research regimen and approaches involve the use of various dengue proteins in understanding molecular mechanisms, drug development and evolutionary aspects. Considering this requirements, we compiled a repository of all available inhibitors which can act as potential targets for the drug discovery. These inhibitors have been linked to various useful attributes such as with multiple features such as pubchem Ids, SMILES, toxicity values with all available IC50, EC50 and CC50 values and in some cases Ki values. Moreover,the server is unique in itself and maintains latest information related to dengue virus inhibitor mainly NS3 and NS5 and updated on regular basis.
1. World Health Organization. Impact of Dengue. Available at http://www.who.int/csr/disease/dengue/impact/en/index.html. Accessed: 10 Oct 2019.
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3. Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis. 2012. 6 (8):e1760.
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6. Chambers TJ, Hahn CS, Galler R, Rice CM. Flavivirus genome organization, expression, and replication. Annual review of microbiology. 1990 Oct;44(1):649-88.
7. Dwivedi VD, Tripathi IP, Tripathi RC, Bharadwaj S, Mishra SK. Genomics, proteomics and evolution of dengue virus. Briefings in functional genomics. 2017 Jul 1;16(4):217-27.
8. Leung JY, Pijlman GP, Kondratieva N, Hyde J, Mackenzie JM, Khromykh AA. Role of nonstructural protein NS2A in flavivirus assembly. Journal of virology. 2008 May 15;82(10):4731-41.
9. Pan A, Saw WG, Manimekalai S, Grüber A, Joon S, Matsui T, Weiss TM, Grüber G. Structural features of NS3 of Dengue virus serotypes 2 and 4 in solution and insight into RNA binding and the inhibitory role of quercetin. Acta Crystallographica Section D: Structural Biology. 2017 May 1;73(5):402-19.
10. Teo CS, Chu JJ. Cellular vimentin regulates construction of dengue virus replication complexes through interaction with NS4A protein. Journal of virology. 2014 Feb 15;88(4):1897-913.
11. Zou J, Xie X, Wang QY, Dong H, Lee MY, Kang C, Yuan Z, Shi PY. Characterization of dengue virus NS4A and NS4B protein interaction. Journal of virology. 2015 Apr 1;89(7):3455-70.
12. Miller S, Kastner S, Krijnse-Locker J, Bühler S, Bartenschlager R. The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner. Journal of Biological Chemistry. 2007 Mar 23;282(12):8873-82.
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