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      Anti-dengue drug: viral polyprotein, a potential target

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      Drug Design, Development and Therapy

      Dove Medical Press

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          Abstract

          Dear editor We would like to add our views regarding the article “Identification of covalent active site inhibitors of dengue virus protease” by Koh-Stenta et al.1 The article suggests the development of a possible drug to combat dengue virus. The drug will inhibit the ability of the virus to replicate by inhibiting the protease enzyme of the virus. The genome of dengue virus is a single-stranded, positive-sense RNA that encodes for a polyprotein. The polyprotein is translated into three structural components, namely capsid, envelope, and membrane, and seven nonstructural proteins, namely NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. NS3 is a serine protease that has a critical role alongside host cell proteases in the protein breakdown of viral polyprotein that leads to replication.2 The foundation of Koh-Stenta et al’s study was fundamentally based on the similarity of the amino acid sequence of proteases, especially at the active sites, of the dengue virus and the West Nile virus.3 As extensive knowledge was available on the West Nile virus and peptide-bound X-ray crystal structure confirmed many protein–ligand interactions similar to the two viruses,4 the knowledge could be applied on dengue virus. The results of Koh-Stenta et al’s research are highly encouraging and show a possibility for the development of an anti-dengue drug in the near future. Another recent study by Dutch investigators suggested that a protein manufactured by the dengue virus NS4B would make a plausible target for antiviral drug.5 Their data suggested that a metabolite of acetaminophen (a common pain killer) AM404 was able to inhibit dengue virus replication. In our opinion, this is a ground-breaking discovery, and the study not only brings us one step closer to the development of an antiviral drug against dengue virus, but also enables the determination of when the replication of the virus is inhibited. The latter was achieved by using a derivative of dengue virus that expressed luciferase, a molecule that produces bioluminescence, during replication. Hence, by correlating the two studies, we conclude that two proteins, ie, NS4B and NS2B, are potential targets for the development of an anti-dengue drug. Moreover, other areas should be explored, of the viral genome, to target other potential sites for drug development. It could be possible to manufacture drugs that stop the virus from entering the cell (entry inhibitors) or drugs that inhibit the strand of RNA (5′ capping) inhibiting viral replication.6

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          Molecular targets for flavivirus drug discovery.

          Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research.
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            Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404.

            Despite the enormous disease burden associated with dengue virus infections, a licensed antiviral drug is lacking. Here, we show that the paracetamol (acetaminophen) metabolite AM404 inhibits dengue virus replication. Moreover, we find that mutations in NS4B that were previously found to confer resistance to the antiviral compounds NITD-618 and SDM25N also render dengue virus insensitive to AM404. Our work provides further support for NS4B as a direct or indirect target for antiviral drug development.
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              Identification of covalent active site inhibitors of dengue virus protease

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                24 June 2016
                : 10
                : 2047-2048
                Affiliations
                Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan
                Author notes
                Correspondence: Syed Uzair Mahmood, 43-8-D, Block 6, PECHS, Karachi 75400, Pakistan, Tel +92 33 1846 1557, Email uzair.hbb@ 123456gmail.com
                Article
                dddt-10-2047
                10.2147/DDDT.S113373
                4928654
                27445456
                © 2016 Mahmood et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Letter

                Pharmacology & Pharmaceutical medicine

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