Ten years of dengue drug discovery: Progress and prospects

doi:10.1016/J.ANTIVIRAL.2013.09.013

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Ten years of dengue drug discovery: Progress and prospects

Journal Article•DOI•

Ten years of dengue drug discovery: Progress and prospects

Siew Pheng Lim¹, Qing Yin Wang², Christian G. Noble², Yen Liang Chen², Hongping Dong², Bin Zou², Fumiaki Yokokawa², Shahul Nilar², Paul Smith², David Beer², Julien Lescar³, Pei Yong Shi² - Show less +8 more•Institutions (3)

Novartis Institute for Tropical Diseases¹, Novartis², Nanyang Technological University³

01 Nov 2013-Antiviral Research (Elsevier)-Vol. 100, Iss: 2, pp 500-519

TL;DR: The knowledge accumulated during the past decade has provided a better rationale for ongoing dengue drug discovery and it is optimistic that this continuous, concerted effort will lead to an effective d Dengue therapy.

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About: This article is published in Antiviral Research.The article was published on 2013-11-01. It has received 305 citations till now. The article focuses on the topics: Balapiravir & Dengue virus.

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Journal Article•DOI•

Zika virus: History, emergence, biology, and prospects for control.

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Scott C. Weaver, Federico Costa¹, Mariano A. Garcia-Blanco², Albert I. Ko³, Guilherme S. Ribeiro¹, George R. Saade², Pei Yong Shi², Nikos Vasilakis² - Show less +4 more•Institutions (3)

Federal University of Bahia¹, University of Texas Medical Branch², Yale University³

01 Jun 2016-Antiviral Research

TL;DR: Zika virus (ZIKV), a previously obscure flavivirus closely related to dengue, West Nile, Japanese encephalitis and yellow fever viruses, has emerged explosively since 2007 to cause a series of epidemics in Micronesia, the South Pacific, and most recently the Americas as discussed by the authors.

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560 citations

Cites background from "Ten years of dengue drug discovery:..."

...No clinically approved therapy is currently available for treatment of any flavivirus infections (Lim et al., 2013)....
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Journal Article•DOI•

Therapeutic Potential of Spirooxindoles as Antiviral Agents.

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Na Ye¹, Haiying Chen¹, Eric A. Wold¹, Pei Yong Shi¹, Jia Zhou¹ - Show less +1 more•Institutions (1)

University of Texas Medical Branch¹

05 May 2016-ACS Infectious Diseases

TL;DR: This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure-activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.

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Abstract: Antiviral therapeutics with profiles of high potency, low resistance, panserotype, and low toxicity remain challenging, and obtaining such agents continues to be an active area of therapeutic development. Due to their unique three-dimensional structural features, spirooxindoles have been identified as privileged chemotypes for antiviral drug development. Among them, spiro-pyrazolopyridone oxindoles have been recently reported as potent inhibitors of dengue virus NS4B, leading to the discovery of an orally bioavailable preclinical candidate (R)-44 with excellent in vivo efficacy in a dengue viremia mouse model. This review highlights recent advances in the development of biologically active spirooxindoles for their antiviral potential, primarily focusing on the structure–activity relationships (SARs) and modes of action, as well as future directions to achieve more potent analogues toward a viable antiviral therapy.

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303 citations

Journal Article•DOI•

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection

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Shuhei Taguwa¹, Kevin Maringer², Kevin Maringer³, Xiaokai Li⁴, Dabeiba Bernal-Rubio³, Jennifer N. Rauch⁴, Jason E. Gestwicki⁴, Raul Andino⁴, Ana Fernandez-Sesma³, Judith Frydman¹ - Show less +6 more•Institutions (4)

Stanford University¹, University of Bristol², Icahn School of Medicine at Mount Sinai³, University of California, San Francisco⁴

19 Nov 2015-Cell

TL;DR: An allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells.

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219 citations

Cites background from "Ten years of dengue drug discovery:..."

...Despite its burden on global health, no specific antivirals or vaccines are licensed for human use (Lim et al., 2013)....
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Journal Article•DOI•

The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development.

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Dahai Luo¹, Subhash G. Vasudevan², Julien Lescar³, Julien Lescar¹•Institutions (3)

Nanyang Technological University¹, National University of Singapore², French Institute of Health and Medical Research³

01 Jun 2015-Antiviral Research

TL;DR: The NS2B-NS3 protein is associated with the endoplasmic reticulum membrane via its close interaction with the central hydrophilic region of the integral membrane protein this article.

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218 citations

Cites background or methods from "Ten years of dengue drug discovery:..."

...While HCV NS3hel has been extensively studied, and several inhibitors have been reported (Lim et al., 2013), the lack of specific pockets at the RNA and at the NTP binding sites is likely to lead to significant toxicity, as compounds targeting these sites might also bind to many similar cellular proteins with helicase/NTPase activities....
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...Therefore, in principle, functional inhibition of the viral NS proteins and/or disruption of the RC underlie targetbased anti-flavivirus drug development (Bollati et al., 2010; Lim et al., 2013; Noble and Shi, 2012; Sampath and Padmanabhan, 2009)....
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...NS3 protease inhibitors are currently designed by either competing with substrate binding or by disrupting the interaction between NS2B and the NS3 protease domain, for a recent review see (Lim et al., 2013)....
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...Here we extend previous reviews by adding some of the new developments on the biology of the flavivirus NS2B–NS3 enzyme, including its interactions with viral proteins NS5 and NS4B and recent antiviral drug development not covered in (Lescar et al., 2008b; Li et al., 2014a; Lim et al., 2013)....
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...While HCV NS3hel has been extensively studied, and several inhibitors have been reported (Lim et al., 2013), the lack of specific pockets at the RNA and at the NTP binding sites is likely to lead to significant toxicity, as compounds targeting these sites might also bind to many similar cellular…...
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Journal Article•DOI•

A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication

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Yongqian Zhao¹, Tingjin Sherryl Soh², Jie Zheng³, Kitti Wing Ki Chan¹, Wint Wint Phoo³, Chin Chin Lee¹, Moon Y. F. Tay¹, Kunchithapadam Swaminathan¹, Tobias Cornvik³, Siew Pheng Lim², Pei Yong Shi², Julien Lescar³, Subhash G. Vasudevan¹, Dahai Luo³ - Show less +10 more•Institutions (3)

National University of Singapore¹, Novartis Institute for Tropical Diseases², Nanyang Technological University³

16 Mar 2015-PLOS Pathogens

TL;DR: A picture for the molecular origin of NS5 flexibility is emerging with profound implications for flavivirus replication and for the development of therapeutics targeting NS5.

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Abstract: Flavivirus RNA replication occurs within a replication complex (RC) that assembles on ER membranes and comprises both non-structural (NS) viral proteins and host cofactors. As the largest protein component within the flavivirus RC, NS5 plays key enzymatic roles through its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent-RNA polymerase (RdRp) domains, and constitutes a major target for antivirals. We determined a crystal structure of the full-length NS5 protein from Dengue virus serotype 3 (DENV3) at a resolution of 2.3 A in the presence of bound SAH and GTP. Although the overall molecular shape of NS5 from DENV3 resembles that of NS5 from Japanese Encephalitis Virus (JEV), the relative orientation between the MTase and RdRp domains differs between the two structures, providing direct evidence for the existence of a set of discrete stable molecular conformations that may be required for its function. While the inter-domain region is mostly disordered in NS5 from JEV, the NS5 structure from DENV3 reveals a well-ordered linker region comprising a short 310 helix that may act as a swivel. Solution Hydrogen/Deuterium Exchange Mass Spectrometry (HDX-MS) analysis reveals an increased mobility of the thumb subdomain of RdRp in the context of the full length NS5 protein which correlates well with the analysis of the crystallographic temperature factors. Site-directed mutagenesis targeting the mostly polar interface between the MTase and RdRp domains identified several evolutionarily conserved residues that are important for viral replication, suggesting that inter-domain cross-talk in NS5 regulates virus replication. Collectively, a picture for the molecular origin of NS5 flexibility is emerging with profound implications for flavivirus replication and for the development of therapeutics targeting NS5.

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216 citations

Cites methods from "Ten years of dengue drug discovery:..."

...The former uses the viral UTR sequence as template to start a new RNA chain while the latter employs an heteropolymeric RNA template annealed with four primers, which is extended during the course of the assay [28,49]....
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...The de novo initiation/elongation assay was described [28,49]....
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References

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Journal Article•DOI•

The global distribution and burden of dengue

[...]

Samir Bhatt¹, Peter W. Gething¹, Oliver J. Brady¹, Jane P. Messina¹, Andrew Farlow¹, Catherine L. Moyes¹, John M. Drake², John M. Drake¹, John S. Brownstein³, Anne G. Hoen⁴, Osman Sankoh⁵, Osman Sankoh⁶, Monica F. Myers¹, Dylan B. George⁷, Thomas Jaenisch⁵, G. R. William Wint¹, Cameron P. Simmons¹, Thomas W. Scott⁸, Thomas W. Scott⁷, Jeremy Farrar¹, Jeremy Farrar⁹, Simon I. Hay⁷, Simon I. Hay¹ - Show less +19 more•Institutions (9)

University of Oxford¹, University of Georgia², Boston Children's Hospital³, Dartmouth College⁴, Heidelberg University⁵, University of the Witwatersrand⁶, National Institutes of Health⁷, University of California, Davis⁸, National University of Singapore⁹

25 Apr 2013-Nature

TL;DR: These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

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Abstract: Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

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7,238 citations

Journal Article•DOI•

Lead- and drug-like compounds: the rule-of-five revolution.

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Christopher A. Lipinski¹•Institutions (1)

Pfizer¹

01 Dec 2004-Drug Discovery Today: Technologies

TL;DR: This topic is explored in terms ofDrug-like physicochemical features, drug-like structural features, a comparison of drug- like and non-drug-like in drug discovery and a discussion of how drug-Like features relate to clinical success.

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3,499 citations

Journal Article•DOI•

Structure of dengue virus: implications for flavivirus organization, maturation, and fusion.

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Richard J. Kuhn¹, Wei Zhang¹, Michael G. Rossmann¹, Sergei V. Pletnev¹, Jeroen Corver², Edith M. Lenches², Christopher T. Jones¹, Suchetana Mukhopadhyay¹, Paul R. Chipman¹, Ellen G. Strauss², Timothy S. Baker¹, James H. Strauss² - Show less +8 more•Institutions (2)

Purdue University¹, California Institute of Technology²

08 Mar 2002-Cell

TL;DR: The first structure of a flavivirus has been determined by using a combination of cryoelectron microscopy and fitting of the known structure of glycoprotein E into the electron density map, suggesting that flaviviruses employ a fusion mechanism in which the distal beta barrels of domain II of the glycop Protein E are inserted into the cellular membrane.

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1,477 citations

"Ten years of dengue drug discovery:..." refers background in this paper

...Structural proteins form the virion: the C protein encapsulates the viral genomic RNA to form the nucleocapsid, and the nucleocapsid is enveloped by a lipid bilayer, in which viral prM and E proteins are embedded (Kuhn et al., 2002)....
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Journal Article•DOI•

The envelope glycoprotein from tick-borne encephalitis virus at 2 Å resolution

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Félix A. Rey¹, Franz X. Heinz², Christian W. Mandl², Christian Kunz², Stephen C. Harrison¹, Stephen C. Harrison³ - Show less +2 more•Institutions (3)

Harvard University¹, University of Vienna², Howard Hughes Medical Institute³

25 May 1995-Nature

TL;DR: The clustering of mutations that affect virulence in various flaviviruses indicates a possible receptor binding site and, together with other mutational and biochemical data, suggests a picture for the fusion-activating, conformational change triggered by low pH.

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Abstract: The crystallographically determined structure of a soluble fragment from the major envelope protein of a flavivirus reveals an unusual architecture. The flat, elongated dimer extends in a direction that would be parallel to the viral membrane. Residues that influence binding of monoclonal antibodies lie on the outward-facing surface of the protein. The clustering of mutations that affect virulence in various flaviviruses indicates a possible receptor binding site and, together with other mutational and biochemical data, suggests a picture for the fusion-activating, conformational change triggered by low pH.

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1,427 citations

"Ten years of dengue drug discovery:..." refers background or methods in this paper

...The structures of the E (Modis et al., 2003; Rey et al., 1995), prM (Li et al., 2008), and C (Ma et al., 2004a) proteins have been solved by X-ray crystallography or NMR (reviewed in (Perera and Kuhn, 2008))....
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...…the structures of other DENV proteins or the same proteins of other flaviviruses solved by various academic groups (Egloff et al., 2002; Li et al., 2008; Ma et al., 2004b; Malet et al., 2007; Modis et al., 2003, 2004; Rey et al., 1995; Wu et al., 2005) have tremendously enabled DENV drug discovery....
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Journal Article•DOI•

A structural perspective of the flavivirus life cycle

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Suchetana Mukhopadhyay¹, Richard J. Kuhn¹, Michael G. Rossmann¹•Institutions (1)

Purdue University¹

01 Jan 2005-Nature Reviews Microbiology

TL;DR: The structural organization of these viruses and their associated structural proteins has provided insight into the molecular transitions that occur during the viral life cycle, such as assembly, budding, maturation and fusion.

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Abstract: Dengue, Japanese encephalitis, West Nile and yellow fever belong to the Flavivirus genus, which is a member of the Flaviviridae family. They are human pathogens that cause large epidemics and tens of thousands of deaths annually in many parts of the world. The structural organization of these viruses and their associated structural proteins has provided insight into the molecular transitions that occur during the viral life cycle, such as assembly, budding, maturation and fusion. This review focuses mainly on structural studies of dengue virus.

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1,167 citations

"Ten years of dengue drug discovery:..." refers background in this paper

...X-ray crystallography and cryo-electron microscopy studies have revealed that DENV consists of 180 molecules of E and M proteins arranged on a host-derived lipid membrane (Mukhopadhyay et al., 2005)....
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...The structures of mature and immature DENV particles have been solved by cryo-electron microscopy (Mukhopadhyay et al., 2005)....
[...]