Molecular Mechanisms of Antiviral Agents against Dengue Virus

Dengue is a major global health threat causing 390 million dengue infections and 25,000 deaths annually. The lack of efficacy of the licensed Dengvaxia vaccine and the absence of a clinically approved antiviral against dengue virus (DENV) drive the urgent demand for the development of novel anti-DENV therapeutics. Various antiviral agents have been developed and investigated for their anti-DENV activities. This review discusses the mechanisms of action employed by various antiviral agents against DENV. The development of host-directed antivirals targeting host receptors and direct-acting antivirals targeting DENV structural and non-structural proteins are reviewed. In addition, the development of antivirals that target different stages during post-infection such as viral replication, viral maturation, and viral assembly are reviewed. Antiviral agents designed based on these molecular mechanisms of action could lead to the discovery and development of novel anti-DENV therapeutics for the treatment of dengue infections. Evaluations of combinations of antiviral drugs with different mechanisms of action could also lead to the development of synergistic drug combinations for the treatment of dengue at any stage of the infection.

[1]  M. I. Giraldo,et al.  PD1 CD44 antiviral peptide as an inhibitor of the protein-protein interaction in dengue virus invasion , 2022, Peptides.

[2]  D. Missé,et al.  Characterization of dengue virus 3’UTR RNA binding proteins in mosquitoes reveals that AeStaufen reduces subgenomic flaviviral RNA in saliva , 2022, bioRxiv.

[3]  D. Jans,et al.  High Throughput Screening Targeting the Dengue NS3-NS5 Interface Identifies Antivirals against Dengue, Zika and West Nile Viruses , 2022, Cells.

[4]  K. Tsukiyama-Kohara,et al.  Mammalian animal models for dengue virus infection: a recent overview , 2021, Archives of virology.

[5]  Peggy Geluykens,et al.  A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction , 2021, Nature.

[6]  P. Bagchi,et al.  Dengue Virus Infection: A Tale of Viral Exploitations and Host Responses , 2021, Viruses.

[7]  Daniel J. Deredge,et al.  Current Trends and Limitations in Dengue Antiviral Research , 2021, Tropical medicine and infectious disease.

[8]  Pravindra Kumar,et al.  Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens , 2021, Bioorganic & Medicinal Chemistry.

[9]  V. Lee,et al.  Cordycepin Inhibits Virus Replication in Dengue Virus-Infected Vero Cells , 2021, Molecules.

[10]  Wei Zheng,et al.  Drug combination therapy for emerging viral diseases , 2021, Drug Discovery Today.

[11]  Ashley N Brown,et al.  Antiviral Evaluation of UV-4B and Interferon-Alpha Combination Regimens against Dengue Virus , 2021, Viruses.

[12]  G. Bonamy,et al.  NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models , 2021, Science Translational Medicine.

[13]  S. Sagan,et al.  Molecular Determinants of Flavivirus Virion Assembly. , 2021, Trends in biochemical sciences.

[14]  Tesia M. Bobrowski,et al.  Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 , 2020, Molecular Therapy.

[15]  J. Smit,et al.  Recent advances in antiviral drug development towards dengue virus. , 2020, Current opinion in virology.

[16]  P. Yenchitsomanus,et al.  Peptides targeting dengue viral nonstructural protein 1 inhibit dengue virus production , 2020, Scientific Reports.

[17]  Z. Zhou,et al.  Structural basis for STAT2 suppression by flavivirus NS5 , 2020, Nature Structural & Molecular Biology.

[18]  I. Kurane,et al.  Non-Human Primate Models of Dengue Virus Infection: A Comparison of Viremia Levels and Antibody Responses during Primary and Secondary Infection among Old World and New World Monkeys , 2020, Pathogens.

[19]  S. Vasudevan,et al.  Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase. , 2020, ACS medicinal chemistry letters.

[20]  Xinwen Chen,et al.  Dengue NS2A Protein Orchestrates Virus Assembly. , 2019, Cell host & microbe.

[21]  J. Chu,et al.  Antiviral activity of ST081006 against the Dengue virus. , 2019, Antiviral research.

[22]  M. Shirouzu,et al.  Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase , 2019, PLoS neglected tropical diseases.

[23]  H. Rothan,et al.  Carnosine exhibits significant antiviral activity against Dengue and Zika virus , 2019, Journal of peptide science : an official publication of the European Peptide Society.

[24]  Neha S. Gandhi,et al.  Dual targeting of dengue virus virions and NS1 protein with the heparan sulfate mimic PG545. , 2019, Antiviral research.

[25]  U. Palanisamy,et al.  Efficacy of geraniin on dengue virus type-2 infected BALB/c mice , 2019, Virology journal.

[26]  P. Bisch,et al.  Dengue virus nonstructural 3 protein interacts directly with human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and reduces its glycolytic activity , 2019, Scientific Reports.

[27]  Gijs J. Overheul,et al.  Escape Mutations in NS 4 B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM 404 , 2019 .

[28]  J. Ludert,et al.  The Dengue Virus Nonstructural Protein 1 (NS1) Is Secreted from Mosquito Cells in Association with the Intracellular Cholesterol Transporter Chaperone Caveolin Complex , 2018, Journal of Virology.

[29]  Sindhoora Bhargavi Gopala Reddy,et al.  Dengue virus NS2 and NS4: Minor proteins, mammoth roles , 2018, Biochemical pharmacology.

[30]  Y. Orba,et al.  Identification of Compound‐B, a novel anti‐dengue virus agent targeting the non‐structural protein 4A , 2018, Antiviral research.

[31]  Dong-ying Fan,et al.  Peptides P4 and P7 derived from E protein inhibit entry of dengue virus serotype 2 via interacting with &bgr;3 integrin , 2018, Antiviral research.

[32]  Jessica L Smith,et al.  Characterization and structure‐activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions , 2018, Antiviral research.

[33]  M. Garcia-Blanco,et al.  Identification and characterization of host proteins bound to dengue virus 3′ UTR reveal an antiviral role for quaking proteins , 2018, RNA.

[34]  J. Low,et al.  Preclinical Antiviral Testing for Dengue Virus Infection in Mouse Models and Its Association with Clinical Studies. , 2018, ACS infectious diseases.

[35]  S. O. Ferreira,et al.  The antimicrobial peptide HS-1 inhibits dengue virus infection. , 2018, Virology.

[36]  J. Low,et al.  Dengue Antiviral Development: A Continuing Journey. , 2018, Advances in Experimental Medicine and Biology.

[37]  U. Palanisamy,et al.  Geraniin extracted from the rind of Nephelium lappaceum binds to dengue virus type-2 envelope protein and inhibits early stage of virus replication , 2017, Virology Journal.

[38]  K. Morita,et al.  Identification of novel antiviral of fungus-derived brefeldin A against dengue viruses , 2017, Tropical Medicine and Health.

[39]  C. Poh,et al.  Peptides as Therapeutic Agents for Dengue Virus , 2017, International journal of medical sciences.

[40]  Peggy Geluykens,et al.  Characterization of a dengue NS4B inhibitor originating from an HCV small molecule library , 2017, Antiviral research.

[41]  W. Hsu,et al.  Bovine Lactoferrin Inhibits Dengue Virus Infectivity by Interacting with Heparan Sulfate, Low-Density Lipoprotein Receptor, and DC-SIGN , 2017, International journal of molecular sciences.

[42]  S. Tajima,et al.  Hirsutine, an Indole Alkaloid of Uncaria rhynchophylla, Inhibits Late Step in Dengue Virus Lifecycle , 2017, Front. Microbiol..

[43]  A. Mawson,et al.  Neglected Tropical Diseases: Epidemiology and Global Burden , 2017, Tropical medicine and infectious disease.

[44]  M. Garcia-Blanco,et al.  The 5′ and 3′ Untranslated Regions of the Flaviviral Genome , 2017, Viruses.

[45]  N. Vasilakis,et al.  Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond , 2017, Nature Reviews Drug Discovery.

[46]  W. Bujalowski,et al.  Interactions between the Dengue Virus Polymerase NS5 and Stem-Loop A , 2017, Journal of Virology.

[47]  Juan Camilo Castrillón-Betancur,et al.  Overexpression of miR-484 and miR-744 in Vero cells alters Dengue virus replication , 2017, Memorias do Instituto Oswaldo Cruz.

[48]  Hsien-Da Huang,et al.  Honeysuckle aqueous extract and induced let-7a suppress dengue virus type 2 replication and pathogenesis. , 2017, Journal of ethnopharmacology.

[49]  J. Lescar,et al.  Dengue Virus Non-Structural Protein 5 , 2014, Viruses.

[50]  A. Gamarnik,et al.  Properties and Functions of the Dengue Virus Capsid Protein. , 2016, Annual review of virology.

[51]  A. Balasubramanian,et al.  High-throughput screening for the identification of small-molecule inhibitors of the flaviviral protease. , 2016, Antiviral research.

[52]  Jacky Flipse,et al.  Antibody-Dependent Enhancement of Dengue Virus Infection in Primary Human Macrophages; Balancing Higher Fusion against Antiviral Responses , 2016, Scientific Reports.

[53]  S. Tajima,et al.  Novel antiviral activity of bromocriptine against dengue virus replication. , 2016, Antiviral research.

[54]  Priscilla L. Yang,et al.  Lactimidomycin is a broad-spectrum inhibitor of dengue and other RNA viruses. , 2016, Antiviral research.

[55]  R. V. van Rij,et al.  Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404 , 2016, Antimicrobial Agents and Chemotherapy.

[56]  Cameron P. Simmons,et al.  Lovastatin for the Treatment of Adult Patients With Dengue: A Randomized, Double-Blind, Placebo-Controlled Trial , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[57]  R. Bartenschlager,et al.  Discovery of Nanomolar Dengue and West Nile Virus Protease Inhibitors Containing a 4-Benzyloxyphenylglycine Residue. , 2015, Journal of medicinal chemistry.

[58]  G. S. St Laurent,et al.  Complex interaction between dengue virus replication and expression of miRNA-133a , 2015, BMC Infectious Diseases.

[59]  P. Yenchitsomanus,et al.  A Peptide Inhibitor Derived from the Conserved Ectodomain Region of DENV Membrane (M) Protein with Activity Against Dengue Virus Infection , 2015, Chemical biology & drug design.

[60]  S. Vasudevan,et al.  Animal models for studying dengue pathogenesis and therapy. , 2015, Antiviral research.

[61]  L. Delang,et al.  Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus , 2015 .

[62]  M. Rajik,et al.  Anti‐dengue virus serotype 2 activity and mode of action of a novel peptide , 2015, Journal of applied microbiology.

[63]  R. Bartenschlager,et al.  Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors. , 2015, Journal of medicinal chemistry.

[64]  Nicholas Jackson,et al.  Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. , 2015, The New England journal of medicine.

[65]  S. Vasudevan,et al.  Structure‐guided Discovery of a Novel Non‐peptide Inhibitor of Dengue Virus NS2B–NS3 Protease , 2015, Chemical biology & drug design.

[66]  S. M. Akula,et al.  Beyond RGD: virus interactions with integrins , 2015, Archives of Virology.

[67]  G. Chang,et al.  Generation of Monoclonal Antibodies against Dengue Virus Type 4 and Identification of Enhancing Epitopes on Envelope Protein , 2015, PloS one.

[68]  Xu Shen,et al.  Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells , 2015, Acta Pharmacologica Sinica.

[69]  Susan A. Jones,et al.  Identification and Characterization of Novel Broad-Spectrum Inhibitors of the Flavivirus Methyltransferase. , 2015, ACS infectious diseases.

[70]  David L. Smith,et al.  The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus , 2015, eLife.

[71]  B. Geiss,et al.  Murine Efficacy and Pharmacokinetic Evaluation of the Flaviviral NS5 Capping Enzyme 2-Thioxothiazolidin-4-One Inhibitor BG-323 , 2015, PloS one.

[72]  Dahai Luo,et al.  The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development. , 2015, Antiviral research.

[73]  Jun Yu Li,et al.  Cellular microRNA-miR-548g-3p modulates the replication of dengue virus. , 2015, The Journal of infection.

[74]  Paul W Smith,et al.  Discovery of Dengue Virus NS4B Inhibitors , 2015, Journal of Virology.

[75]  Hongmin Li,et al.  5'-Silylated 3'-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus. , 2015, Journal of medicinal chemistry.

[76]  Neerja Kaushik-Basu,et al.  Characterization of the activity of 2'-C-methylcytidine against dengue virus replication. , 2015, Antiviral research.

[77]  Alicia M. Hanson,et al.  Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. , 2015, ACS infectious diseases.

[78]  Dahai Luo,et al.  A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication , 2015, PLoS pathogens.

[79]  Marco M. Domingues,et al.  Understanding dengue virus capsid protein disordered N-Terminus and pep14-23-based inhibition. , 2015, ACS chemical biology.

[80]  B. Kümmerer,et al.  A Basic Cluster in the N Terminus of Yellow Fever Virus NS2A Contributes to Infectious Particle Production , 2015, Journal of Virology.

[81]  P. Yogeeswari,et al.  A small molecule inhibitor of dengue virus type 2 protease inhibits the replication of all four dengue virus serotypes in cell culture , 2015, Virology Journal.

[82]  G. Carrasquilla,et al.  Efficacy of a tetravalent dengue vaccine in children in Latin America. , 2015, The New England journal of medicine.

[83]  Ralf Bartenschlager,et al.  Novel Dengue Virus NS2B/NS3 Protease Inhibitors , 2014, Antimicrobial Agents and Chemotherapy.

[84]  D. Gubler,et al.  Review article: Research on dengue during World War II revisited. , 2014, The American journal of tropical medicine and hygiene.

[85]  Devika Sirohi,et al.  Coupling of replication and assembly in flaviviruses. , 2014, Current opinion in virology.

[86]  Subhash G. Vasudevan,et al.  Suramin inhibits helicase activity of NS3 protein of dengue virus in a fluorescence-based high throughput assay format. , 2014, Biochemical and biophysical research communications.

[87]  P. Pitisuttithum,et al.  Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial , 2014, The Lancet.

[88]  J. Connolly,et al.  Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. , 2014, The Lancet. Infectious diseases.

[89]  P. Yenchitsomanus,et al.  Peptide Inhibitors Against Dengue Virus Infection , 2014, Chemical biology & drug design.

[90]  Chelsea M. Byrd,et al.  Characterization of the Mode of Action of a Potent Dengue Virus Capsid Inhibitor , 2014, Journal of Virology.

[91]  Rohana Yusof,et al.  Identification of natural antimicrobial agents to treat dengue infection: In vitro analysis of latarcin peptide activity against dengue virus , 2014, BMC Microbiology.

[92]  Gianluca Pegoraro,et al.  Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430 , 2014, Nature.

[93]  Thomas Walker,et al.  Limited Dengue Virus Replication in Field-Collected Aedes aegypti Mosquitoes Infected with Wolbachia , 2014, PLoS neglected tropical diseases.

[94]  A. Maciuk,et al.  New Inhibitors of the DENV-NS 5 RdRp from Carpolepis laurifolia as Potential Antiviral Drugs for Dengue Treatment , 2014 .

[95]  A. Amara,et al.  Flavivirus Entry Receptors: An Update , 2013, Viruses.

[96]  G. Wang,et al.  Activation of Peripheral Blood Mononuclear Cells by Dengue Virus Infection Depotentiates Balapiravir , 2013, Journal of Virology.

[97]  David Beer,et al.  Ten years of dengue drug discovery: progress and prospects. , 2013, Antiviral research.

[98]  Qianjun Li,et al.  The interaction between claudin-1 and dengue viral prM/M protein for its entry. , 2013, Virology.

[99]  T. Yasunaga,et al.  A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication. , 2013, Biochemical and biophysical research communications.

[100]  A. Yueh,et al.  A Novel Dengue Virus Inhibitor, BP13944, Discovered by High-Throughput Screening with Dengue Virus Replicon Cells Selects for Resistance in the Viral NS2B/NS3 Protease , 2013, Antimicrobial Agents and Chemotherapy.

[101]  T. Pierson,et al.  Nucleolin Interacts with the Dengue Virus Capsid Protein and Plays a Role in Formation of Infectious Virus Particles , 2013, Journal of Virology.

[102]  S. Chakravarty,et al.  Structural, Antigenic, and Evolutionary Characterizations of the Envelope Protein of Newly Emerging Duck Tembusu Virus , 2013, PloS one.

[103]  John A. Young,et al.  Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. , 2013, Cell host & microbe.

[104]  E. Harris,et al.  Symptomatic Versus Inapparent Outcome in Repeat Dengue Virus Infections Is Influenced by the Time Interval between Infections and Study Year , 2013, PLoS neglected tropical diseases.

[105]  C. Huang,et al.  Mutation of the dengue virus type 2 envelope protein heparan sulfate binding sites or the domain III lateral ridge blocks replication in Vero cells prior to membrane fusion. , 2013, Virology.

[106]  Yee‐Shin Lin,et al.  An emerging role for the anti-inflammatory cytokine interleukin-10 in dengue virus infection , 2013, Journal of Biomedical Science.

[107]  E. Harris,et al.  Original antigenic sin in dengue revisited , 2013, Proceedings of the National Academy of Sciences.

[108]  P. Young,et al.  The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. , 2013, Antiviral research.

[109]  Victor A. Kostyuchenko,et al.  Immature and Mature Dengue Serotype 1 Virus Structures Provide Insight into the Maturation Process , 2013, Journal of Virology.

[110]  Priscilla L. Yang,et al.  The Small Molecules AZD0530 and Dasatinib Inhibit Dengue Virus RNA Replication via Fyn Kinase , 2013, Journal of Virology.

[111]  A. K. Rathinam,et al.  Inhibition of Dengue Virus Entry into Target Cells Using Synthetic Antiviral Peptides , 2013, International journal of medical sciences.

[112]  N. Nomura,et al.  Sulfated Polysaccharide, Curdlan Sulfate, Efficiently Prevents Entry/Fusion and Restricts Antibody-Dependent Enhancement of Dengue Virus Infection In Vitro: A Possible Candidate for Clinical Application , 2013, PLoS neglected tropical diseases.

[113]  John S. Brownstein,et al.  The global distribution and burden of dengue , 2013, Nature.

[114]  Masaud Shah,et al.  Interaction and Inhibition of Dengue Envelope Glycoprotein with Mammalian Receptor DC-Sign, an In-Silico Approach , 2013, PloS one.

[115]  Dennis E. Hruby,et al.  Novel Benzoxazole Inhibitor of Dengue Virus Replication That Targets the NS3 Helicase , 2013, Antimicrobial Agents and Chemotherapy.

[116]  Å. Lundkvist,et al.  Dengue viruses – an overview , 2013, Infection ecology & epidemiology.

[117]  B. Canard,et al.  Phytochemical Study of Myrtopsis corymbosa, Perspectives for Anti-dengue Natural Compound Research , 2013 .

[118]  G. Lushington,et al.  Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases. , 2013, Bioorganic & medicinal chemistry.

[119]  S. Harrison,et al.  Structure of a Dengue Virus Envelope Protein Late-Stage Fusion Intermediate , 2012, Journal of Virology.

[120]  B. Canard,et al.  Antiviral chlorinated daphnane diterpenoid orthoesters from the bark and wood of Trigonostemon cherrieri. , 2012, Phytochemistry.

[121]  H. Rothan,et al.  Inhibition of dengue NS2B-NS3 protease and viral replication in Vero cells by recombinant retrocyclin-1 , 2012, BMC Infectious Diseases.

[122]  J. Villalaín,et al.  NS4A and NS4B proteins from dengue virus: membranotropic regions. , 2012, Biochimica et biophysica acta.

[123]  E. Damonte,et al.  Antiviral activity against dengue virus of diverse classes of algal sulfated polysaccharides. , 2012, International journal of biological macromolecules.

[124]  Alicia M. Hanson,et al.  Fluorescent primuline derivatives inhibit hepatitis C virus NS3-catalyzed RNA unwinding, peptide hydrolysis and viral replicase formation. , 2012, Antiviral research.

[125]  O. Schwartz,et al.  The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. , 2012, Cell host & microbe.

[126]  Chelsea M. Byrd,et al.  A Novel Inhibitor of Dengue Virus Replication That Targets the Capsid Protein , 2012, Antimicrobial Agents and Chemotherapy.

[127]  Rohana Yusof,et al.  Protegrin-1 Inhibits Dengue NS2B-NS3 Serine Protease and Viral Replication in MK2 Cells , 2012, Journal of biomedicine & biotechnology.

[128]  B. Canard,et al.  Chemical constituents of Anacolosa pervilleana and their antiviral activities. , 2012, Fitoterapia.

[129]  C. T. Tam,et al.  Effects of Short-Course Oral Corticosteroid Therapy in Early Dengue Infection in Vietnamese Patients: A Randomized, Placebo-Controlled Trial , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[130]  Alicia M. Hanson,et al.  Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. , 2012, The Journal of antimicrobial chemotherapy.

[131]  Franz X Heinz,et al.  Flaviviruses and flavivirus vaccines. , 2012, Vaccine.

[132]  Yee‐Shin Lin,et al.  Endothelial cell surface expression of protein disulfide isomerase activates β1 and β3 integrins and facilitates dengue virus infection , 2012, Journal of cellular biochemistry.

[133]  Tara Kirk Sell,et al.  Return of Epidemic Dengue in the United States: Implications for the Public Health Practitioner , 2012, Public health reports.

[134]  C. Steuer,et al.  Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease. , 2012, Antiviral research.

[135]  S. Harrison,et al.  Small-Molecule Inhibitors of Dengue-Virus Entry , 2012, PLoS pathogens.

[136]  Suzanne M. Tomlinson,et al.  Use of parallel validation high-throughput screens to reduce false positives and identify novel dengue NS2B-NS3 protease inhibitors. , 2012, Antiviral research.

[137]  B. Kobe,et al.  Residues in domain III of the dengue virus envelope glycoprotein involved in cell-surface glycosaminoglycan binding. , 2012, The Journal of general virology.

[138]  B. Canard,et al.  Alkylated flavanones from the bark of Cryptocarya chartacea as dengue virus NS5 polymerase inhibitors. , 2011, Journal of natural products.

[139]  J. Chu,et al.  Narasin, a Novel Antiviral Compound that Blocks Dengue Virus Protein Expression , 2011, Antiviral therapy.

[140]  L. Kramer,et al.  Inhibition of Dengue Virus by Targeting Viral NS4B Protein , 2011, Journal of Virology.

[141]  David C. Chang,et al.  A Translation Inhibitor That Suppresses Dengue Virus In Vitro and In Vivo , 2011, Antimicrobial Agents and Chemotherapy.

[142]  R. Bartenschlager,et al.  Synthesis and biological evaluation of α-ketoamides as inhibitors of the Dengue virus protease with antiviral activity in cell-culture. , 2011, Bioorganic & medicinal chemistry.

[143]  J. Neyts,et al.  Broad Antiviral Activity of Carbohydrate-Binding Agents against the Four Serotypes of Dengue Virus in Monocyte-Derived Dendritic Cells , 2011, PloS one.

[144]  S. Margosiak,et al.  Small Molecule Pan-Dengue and West Nile Virus NS3 Protease Inhibitors , 2011, Antiviral chemistry & chemotherapy.

[145]  E. Damonte,et al.  Differential inhibition of dengue virus infection in mammalian and mosquito cells by iota-carrageenan. , 2011, The Journal of general virology.

[146]  E. Datan,et al.  Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication* , 2011, The Journal of Biological Chemistry.

[147]  E. Gorovits,et al.  INX-08189, a Phosphoramidate Prodrug of 6-O-Methyl-2′-C-Methyl Guanosine, Is a Potent Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic and Pharmacodynamic Properties , 2011, Antimicrobial Agents and Chemotherapy.

[148]  Yen-Liang Chen,et al.  Functional Analysis of Two Cavities in Flavivirus NS5 Polymerase , 2011, The Journal of Biological Chemistry.

[149]  K. Stiasny,et al.  The Unique Transmembrane Hairpin of Flavivirus Fusion Protein E Is Essential for Membrane Fusion , 2011, Journal of Virology.

[150]  M. Martínez-Gutiérrez,et al.  Statins Reduce Dengue Virus Production via Decreased Virion Assembly , 2011, Intervirology.

[151]  Chie Aoki,et al.  Dengue virus type 2 recognizes the carbohydrate moiety of neutral glycosphingolipids in mammalian and mosquito cells , 2011, Microbiology and immunology.

[152]  P. Shi,et al.  Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. , 2011, Antiviral research.

[153]  Gang Wang,et al.  Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase* , 2010, The Journal of Biological Chemistry.

[154]  K. Morita,et al.  Antiviral activity of chondroitin sulphate E targeting dengue virus envelope protein. , 2010, Antiviral research.

[155]  Cameron P. Simmons,et al.  An In-Depth Analysis of Original Antigenic Sin in Dengue Virus Infection , 2010, Journal of Virology.

[156]  A. Yueh,et al.  Novel Dengue Virus-Specific NS2B/NS3 Protease Inhibitor, BP2109, Discovered by a High-Throughput Screening Assay , 2010, Antimicrobial Agents and Chemotherapy.

[157]  M. Kielian,et al.  In Vitro and In Vivo Studies Identify Important Features of Dengue Virus pr-E Protein Interactions , 2010, PLoS pathogens.

[158]  S. Harrison,et al.  Peptide Inhibitors of Flavivirus Entry Derived from the E Protein Stem , 2010, Journal of Virology.

[159]  Gregory D. Gromowski,et al.  Short Communication Characterization of a dengue type-specific epitope on dengue 3 virus envelope protein domain III , 2010 .

[160]  David I. Stuart,et al.  Structure and functionality in flavivirus NS-proteins: Perspectives for drug design , 2010, Antiviral research.

[161]  J. Farrar,et al.  A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults , 2010, PLoS neglected tropical diseases.

[162]  Ram Samudrala,et al.  Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides , 2010, PLoS neglected tropical diseases.

[163]  Zhiming Yuan,et al.  Identification of palmatine as an inhibitor of West Nile virus , 2010, Archives of Virology.

[164]  Yen-Liang Chen,et al.  Inhibition of Dengue Virus RNA Synthesis by an Adenosine Nucleoside , 2010, Antimicrobial Agents and Chemotherapy.

[165]  J. Smit,et al.  Dengue virus life cycle: viral and host factors modulating infectivity , 2010, Cellular and Molecular Life Sciences.

[166]  S. Harrison,et al.  Peptide Inhibitors of Dengue-Virus Entry Target a Late-Stage Fusion Intermediate , 2010, PLoS pathogens.

[167]  M. Liao,et al.  In Vitro Reconstitution Reveals Key Intermediate States of Trimer Formation by the Dengue Virus Membrane Fusion Protein , 2010, Journal of Virology.

[168]  Yen-Liang Chen,et al.  Strategies for development of Dengue virus inhibitors. , 2010, Antiviral research.

[169]  S. Tajima,et al.  Restoration of replication-defective dengue type 1 virus bearing mutations in the N-terminal cytoplasmic portion of NS4A by additional mutations in NS4B , 2010, Archives of Virology.

[170]  E. Harris,et al.  Control of dengue virus translation and replication. , 2010, Current topics in microbiology and immunology.

[171]  A. Caflisch,et al.  A fluorescence quenching assay to discriminate between specific and nonspecific inhibitors of dengue virus protease. , 2009, Analytical biochemistry.

[172]  P. Shi,et al.  A small molecule fusion inhibitor of dengue virus. , 2009, Antiviral research.

[173]  Martin J. Stoermer,et al.  In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses. , 2009, Antiviral research.

[174]  P. Niyomrattanakit,et al.  An adenosine nucleoside inhibitor of dengue virus , 2009, Proceedings of the National Academy of Sciences.

[175]  M. Rossmann,et al.  Association of the pr Peptides with Dengue Virus at Acidic pH Blocks Membrane Fusion , 2009, Journal of Virology.

[176]  E. Damonte,et al.  Alternative infectious entry pathways for dengue virus serotypes into mammalian cells , 2009, Cellular microbiology.

[177]  Yuan-Ping Pang,et al.  Structure-based discovery of dengue virus protease inhibitors. , 2009, Antiviral research.

[178]  Suzanne M. Tomlinson,et al.  New approaches to structure-based discovery of dengue protease inhibitors. , 2009, Infectious disorders drug targets.

[179]  E. Jacoby,et al.  A Small-Molecule Dengue Virus Entry Inhibitor , 2009, Antimicrobial Agents and Chemotherapy.

[180]  S. Swaminathan,et al.  Dengue: recent advances in biology and current status of translational research. , 2009, Current molecular medicine.

[181]  R. Kuhn,et al.  Antiviral compounds discovered by virtual screening of small-molecule libraries against dengue virus E protein. , 2008, ACS chemical biology.

[182]  Wolfgang Jahnke,et al.  Insights into RNA unwinding and ATP hydrolysis by the flavivirus NS3 protein , 2008, The EMBO journal.

[183]  Michael J Rust,et al.  Dissecting the Cell Entry Pathway of Dengue Virus by Single-Particle Tracking in Living Cells , 2008, PLoS pathogens.

[184]  Takashi Suzuki,et al.  Structure and anti-dengue virus activity of sulfated polysaccharide from a marine alga. , 2008, Biochemical and biophysical research communications.

[185]  S. Michael,et al.  In vitro inhibition of dengue virus entry by p-sulfoxy-cinnamic acid and structurally related combinatorial chemistries. , 2008, Antiviral research.

[186]  G. Chinea,et al.  Characterization of the interaction of domain III of the envelope protein of dengue virus with putative receptors from CHO cells. , 2008, Virus research.

[187]  Xiaoqun Duan,et al.  Novel binding between pre-membrane protein and vacuolar ATPase is required for efficient dengue virus secretion. , 2008, Biochemical and biophysical research communications.

[188]  Richard J Kuhn,et al.  Structural proteomics of dengue virus. , 2008, Current opinion in microbiology.

[189]  Wei Zhang,et al.  Structure of the Immature Dengue Virus at Low pH Primes Proteolytic Maturation , 2008, Science.

[190]  Ying Zhang,et al.  The Flavivirus Precursor Membrane-Envelope Protein Complex: Structure and Maturation , 2008, Science.

[191]  R. Dwek,et al.  Correction: The Mannose Receptor Mediates Dengue Virus Infection of Macrophages , 2008, PLoS Pathogens.

[192]  E. Damonte,et al.  Functional entry of dengue virus into Aedes albopictus mosquito cells is dependent on clathrin-mediated endocytosis. , 2008, The Journal of general virology.

[193]  R. Dwek,et al.  The Mannose Receptor Mediates Dengue Virus Infection of Macrophages , 2008, PLoS pathogens.

[194]  R. Kuhn,et al.  Yellow Fever Virus NS3 Plays an Essential Role in Virus Assembly Independent of Its Known Enzymatic Functions , 2008, Journal of Virology.

[195]  Yan-Ping Tian,et al.  Up-regulated expression of beta3 integrin induced by dengue virus serotype 2 infection associated with virus entry into human dermal microvascular endothelial cells. , 2007, Biochemical and biophysical research communications.

[196]  Jinn-Moon Yang,et al.  Combinatorial Computational Approaches to Identify Tetracycline Derivatives as Flavivirus Inhibitors , 2007, PloS one.

[197]  A. Gamarnik,et al.  Essential Role of Dengue Virus Envelope Protein N Glycosylation at Asparagine-67 during Viral Propagation , 2007, Journal of Virology.

[198]  Ralf Bartenschlager,et al.  The Non-structural Protein 4A of Dengue Virus Is an Integral Membrane Protein Inducing Membrane Alterations in a 2K-regulated Manner* , 2007, Journal of Biological Chemistry.

[199]  Christl A Donnelly,et al.  Late-acting dominant lethal genetic systems and mosquito control , 2007, BMC Biology.

[200]  J. Chu,et al.  c-Src protein kinase inhibitors block assembly and maturation of dengue virus , 2007, Proceedings of the National Academy of Sciences.

[201]  H. Agaisse,et al.  Rab 5 Is Required for the Cellular Entry of Dengue and West Nile Viruses , 2007, Journal of Virology.

[202]  D. Ray,et al.  Distinct RNA Elements Confer Specificity to Flavivirus RNA Cap Methylation Events , 2007, Journal of Virology.

[203]  J. Lepault,et al.  Characterization of a Structural Intermediate of Flavivirus Membrane Fusion , 2007, PLoS pathogens.

[204]  Ashish,et al.  Antiviral Peptides Targeting the West Nile Virus Envelope Protein , 2006, Journal of Virology.

[205]  E. Harris,et al.  Recent Advances in Deciphering Viral and Host Determinants of Dengue Virus Replication and Pathogenesis , 2006, Journal of Virology.

[206]  M. Ng,et al.  Analysis of the endocytic pathway mediating the infectious entry of mosquito-borne flavivirus West Nile into Aedes albopictus mosquito (C6/36) cells. , 2006, Virology.

[207]  J. Mackenzie,et al.  Regulated Cleavages at the West Nile Virus NS4A-2K-NS4B Junctions Play a Major Role in Rearranging Cytoplasmic Membranes and Golgi Trafficking of the NS4A Protein , 2006, Journal of Virology.

[208]  Chie Aoki,et al.  Identification and characterization of carbohydrate molecules in mammalian cells recognized by dengue virus type 2. , 2006, Journal of biochemistry.

[209]  D. A. Stein,et al.  Inhibition of dengue virus translation and RNA synthesis by a morpholino oligomer targeted to the top of the terminal 3' stem-loop structure. , 2006, Virology.

[210]  Duncan R. Smith,et al.  Growth and Production of the Dengue Virus in C6/36 Cells and Identification of a Laminin-Binding Protein as a Candidate Serotype 3 and 4 Receptor Protein , 2006, Intervirology.

[211]  M. Pavy,et al.  Antiviral effect of the heparan sulfate mimetic, PI-88, against dengue and encephalitic flaviviruses. , 2006, Antiviral research.

[212]  T. Dreher,et al.  Control of Translation by the 5′- and 3′-Terminal Regions of the Dengue Virus Genome , 2005, Journal of Virology.

[213]  R. Doms,et al.  Castanospermine, a Potent Inhibitor of Dengue Virus Infection In Vitro and In Vivo , 2005, Journal of Virology.

[214]  P. Desprès,et al.  Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN)-mediated Enhancement of Dengue Virus Infection Is Independent of DC-SIGN Internalization Signals* , 2005, Journal of Biological Chemistry.

[215]  E. Damonte,et al.  The antiviral activity of sulfated polysaccharides against dengue virus is dependent on virus serotype and host cell. , 2005, Antiviral research.

[216]  Scott F Michael,et al.  Peptide inhibitors of dengue virus and West Nile virus infectivity , 2005, Virology Journal.

[217]  R. D. del Ángel,et al.  Heat Shock Protein 90 and Heat Shock Protein 70 Are Components of Dengue Virus Receptor Complex in Human Cells , 2005, Journal of Virology.

[218]  C. Thepparit,et al.  Serotype-Specific Entry of Dengue Virus into Liver Cells: Identification of the 37-Kilodalton/67-Kilodalton High-Affinity Laminin Receptor as a Dengue Virus Serotype 1 Receptor , 2004, Journal of Virology.

[219]  E. Harris,et al.  Enhancement of dengue virus translation: role of the 3' untranslated region and the terminal 3' stem-loop domain. , 2004, Virology.

[220]  Giovanni Migliaccio,et al.  A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties , 2004, Antimicrobial Agents and Chemotherapy.

[221]  M. Ng,et al.  Infectious Entry of West Nile Virus Occurs through a Clathrin-Mediated Endocytic Pathway , 2004, Journal of Virology.

[222]  Timothy S Baker,et al.  Conformational changes of the flavivirus E glycoprotein. , 2004, Structure.

[223]  Carol Beth Post,et al.  Solution structure of dengue virus capsid protein reveals another fold. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[224]  K. Stiasny,et al.  Structure of a flavivirus envelope glycoprotein in its low‐pH‐induced membrane fusion conformation , 2004, The EMBO journal.

[225]  Y. Modis,et al.  Structure of the dengue virus envelope protein after membrane fusion , 2004, Nature.

[226]  Wen Chang,et al.  An External Loop Region of Domain III of Dengue Virus Type 2 Envelope Protein Is Involved in Serotype-Specific Binding to Mosquito but Not Mammalian Cells , 2004, Journal of Virology.

[227]  Adolfo García-Sastre,et al.  Inhibition of interferon signaling by dengue virus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[228]  Y. Kawaoka,et al.  Antibody‐dependent enhancement of viral infection: molecular mechanisms and in vivo implications , 2003, Reviews in medical virology.

[229]  T. Geijtenbeek,et al.  Pathogens target DC‐SIGN to influence their fate DC‐SIGN functions as a pathogen receptor with broad specificity , 2003, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[230]  G. Wengler,et al.  The membrane proteins of flaviviruses form ion-permeable pores in the target membrane after fusion: identification of the pores and analysis of their possible role in virus infection. , 2003, The Journal of general virology.

[231]  P. Desprès,et al.  Dendritic‐cell‐specific ICAM3‐grabbing non‐integrin is essential for the productive infection of human dendritic cells by mosquito‐cell‐derived dengue viruses , 2003, EMBO reports.

[232]  Y. Modis,et al.  A ligand-binding pocket in the dengue virus envelope glycoprotein , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[233]  R. Steinman,et al.  DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic Cells , 2003, The Journal of experimental medicine.

[234]  M. Diamond,et al.  Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. , 2002, Virology.

[235]  A. Nisalak,et al.  High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. , 2002, The Journal of infectious diseases.

[236]  Wei Zhang,et al.  Structure of Dengue Virus Implications for Flavivirus Organization, Maturation, and Fusion , 2002, Cell.

[237]  H. Lortat-Jacob,et al.  Heparan sulfate-mediated binding of infectious dengue virus type 2 and yellow fever virus. , 2002, Virology.

[238]  S. Selleck,et al.  Order out of chaos: assembly of ligand binding sites in heparan sulfate. , 2002, Annual review of biochemistry.

[239]  J. Roehrig,et al.  Monoclonal Antibodies That Bind to Domain III of Dengue Virus E Glycoprotein Are the Most Efficient Blockers of Virus Adsorption to Vero Cells , 2001, Journal of Virology.

[240]  P. Hilgard,et al.  Heparan sulfate proteoglycans initiate dengue virus infection of hepatocytes , 2000, Hepatology.

[241]  M. Ng,et al.  A different mode of entry by dengue-2 neutralisation escape mutant virus , 1999, Archives of Virology.

[242]  G. Kuno,et al.  Phylogeny of the Genus Flavivirus , 1998, Journal of Virology.

[243]  F. Heinz,et al.  Proteolytic activation of tick-borne encephalitis virus by furin , 1997, Journal of virology.

[244]  P. Young,et al.  Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. , 1996, Virology.

[245]  C. Rice,et al.  Molecular biology of the flaviviruses. , 1987, Microbiological sciences.