Flaviviral NS4b, chameleon and jack-in-the-box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention

Reviews in Medical Virology

Volumn 25, Issue 4, 2015, Pages 205-223

  Zmurko, Joanna ^a   Neyts, Johan ^a   Dallmeier, Kai ^a  

^a REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; NONSTRUCTURAL PROTEIN 4B; NS4B PROTEIN, FLAVIVIRUS; VIRUS PROTEIN;

DENGUE VIRUS; DRUG TARGETING; FLAVIVIRUS; IMMUNE EVASION; INNATE IMMUNITY; JAPANESE ENCEPHALITIS VIRUS; LIFE CYCLE; NONHUMAN; PATHOGENESIS; PHENOTYPE; PROTEIN INTERACTION; PROTEIN LOCALIZATION; PROTEIN PROCESSING; PROTEIN STRUCTURE; REVIEW; RNA INTERFERENCE; SEROTYPE; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE; VIRUS CELL INTERACTION; VIRUS MUTATION; VIRUS REPLICATION; WEST NILE VIRUS; YELLOW FEVER VIRUS; ANTAGONISTS AND INHIBITORS; HOST PATHOGEN INTERACTION; HUMAN; IMMUNOLOGY; ISOLATION AND PURIFICATION; METABOLISM; PHYSIOLOGY;

ANTIVIRAL AGENTS; FLAVIVIRUS; HOST-PATHOGEN INTERACTIONS; HUMANS; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84935710644     PISSN: 10529276     EISSN: 10991654     Source Type: Journal    
DOI: 10.1002/rmv.1835     Document Type: Review

References (130)

1. WHO. Dengue: guidelines for diagnosis, treatment, prevention, and control. Special Programme for Research and Training in Tropical Diseases 2009. DOI: WHO/HTM/NTD/DEN/2009.1.
2. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. [Internet]. Nature 2013; 496: 504-507.
3. Paper WP. Weekly epidemiological record Relevé épidémiologique hebdomadaire. 2013; 27(88): 269-284. http://www.who.int/wer
4. Quaresma JAS, Pagliari C, Medeiros DBA, Duarte MIS, Vasconcelos PFC. Immunity and immune response, pathology and pathologic changes: progress and challenges in the immunopathology of yellow fever. Reviews in Medical Virology 2013. DOI:10.1002/rmv1752.
5. Pulendran B. Learning immunology from the yellow fever vaccine: innate immunity to systems vaccinology. [Internet]. Nature Reviews Immunology 2009; 9: 741-747.
6. Julander JG. Experimental therapies for yellow fever. [Internet]. Antiviral Research 2013; 97: 169-179.
7. Kramer LD, Li J, Shi P. West Nile virus C prM E. Lancet Neurology 2007; 6(2): 171-181. DOI:10.1016/S1474-4422(07)70030-3.
8. Suthar MS, Diamond MS, Gale M. West Nile virus infection and immunity. [Internet]. Nature Reviews Microbiology 2013; 11: 115-128.
9. Murray KO, Mertens E, Desprès P. West Nile virus and its emergence in the United States of America. [Internet]. Veterinary Research 2010; 41: 67.
10. Campbell GL, Hills SL, Fischer M, et al. Estimated global incidence of Japanese encephalitis: a systematic review. [Internet]. Bulletin of the World Health Organization 2011; 89: 766-774, 774A-774E.
11. Yun S-I, Lee Y-M. Japanese encephalitis: the virus and vaccines. [Internet]. Human Vaccines and Immunotherapeutics 2014; 10: 263-279.
12. Nile W, Encepha- E, Go Y, et al. Clin Exp Vaccine Res 2014; 3(1): 58-77; Doi: 10.7774/cevr.2014.3.1.58. [Epub 2013 Dec 18].
13. Goldenberg MM. Pharmaceutical approval update. Pharmacy and Therapeutics 2008; 33: 362-363.
14. Leyssen P, De Clercq E, Neyts J. Perspectives for the treatment of infections with Flaviviridae. Clinical Microbiology Reviews 2000; 13:(1): 67-82. Doi: 10.1128/CMR.13.1.67-82.2000.
15. Debing Y, Jochmans D, Neyts J. Intervention strategies for emerging viruses: use of antivirals. [Internet]. Current Opinion in Virology 2013; 3: 217-224.
16. Lim SP, Wang Q-Y, Noble CG, et al. Ten years of dengue drug discovery: progress and prospects. [Internet]. Antiviral Research 2013; 100: 500-519.
17. Samsa MM, Mondotte JA, Caramelo JJ, Gamarnik AV. Uncoupling cis-acting RNA elements from coding sequences revealed a requirement of the N-terminal region of dengue virus capsid protein in virus particle formation. [Internet]. Journal of Virology 2012; 86: 1046-1058.
18. Lindenbach BD, Rice CM. Molecular biology of flaviviruses. [Internet]. Advances in Virus Research 2003; 59: 23-61.
19. Sampath A, Padmanabhan R. Molecular targets for flavivirus drug discovery. Antiviral Res 2009; 81: 6-15.
20. Miller S, Krijnse-Locker J. Modification of intracellular membrane structures for virus replication. [Internet]. Nature Reviews Microbiology 2008; 6: 363-374.
21. Falgout B, Miller RH, Lai C. Deletion analysis of dengue virus type 4 nonstructural protein NS2b: identification of a domain required for NS2b-NS3 protease activity. Journal of Virology 1993; 67: 2034-2042.
22. Warrener P, Tamura JK, Collett MS, Watkins W, Road M. RNA-Stimulated NTPase Activity Associated with Yellow Fever Virus NS3 Protein Expressed in Bacteria. Journal of Virology 1993; 67: 989-996.
23. Wengler G. The carboxy-terminal part of the NS 3 protein of the West Nile flavivirus can be isolated as a soluble protein after proteolytic cleavage and represents an RNA-stimulated NTPase. [Internet]. Virology 1991; 184: 707-715.
24. Ackermann M, Padmanabhan R. De novo synthesis of RNA by the dengue virus RNA-dependent RNA polymerase exhibits temperature dependence at the initiation but not elongation phase. The Journal of Biological Chemistry 2001; 276: 39926-39937. doi: 10.1074/jbc.M104248200/jbc
25. Egloff M-P, Benarroch D, Selisko B, Romette J-L, Canard B. An RNA cap (nucleoside-2'-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization. [Internet]. EMBO Journal 2002; 21: 2757-2768.
26. Guyatt KJ, Westaway EG, Khromykh AA. Expression and purification of enzymatically active recombinant RNA-dependent RNA polymerase (NS5) of the flavivirus Kunjin. [Internet]. Journal of Virological Methods 2001; 92: 37-44.
27. Tan BH, Fu J, Sugrue RJ, Yap EH, Chan YC, Tan YH. Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity. [Internet]. Virology 1996; 216: 317-325.
28. Malet H, Massé N, Selisko B, et al. The flavivirus polymerase as a target for drug discovery. [Internet]. Antiviral Research 2008; 80: 23-35.
29. Muller DA, Young PR. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. [Internet]. Antiviral Research 2013; 98: 192-208.
30. Xie X, Wang Q-Y, Xu HY, et al. Inhibition of dengue virus by targeting viral NS4B protein. [Internet]. Journal of Virology 2011; 85: 11183-11195.
31. Miller S, Sparacio S, Bartenschlager R. Subcellular localization and membrane topology of the dengue virus type 2 non-structural protein 4B. [Internet]. Journal of Biological Chemistry 2006; 281: 8854-8863.
32. Zou G, Puig-Basagoiti F, Zhang B, et al. A single-amino acid substitution in West Nile virus 2K peptide between NS4a and NS4b confers resistance to lycorine, a flavivirus inhibitor. [Internet]. Virology 2009; 384: 242-252. DOI:10.1016/j.chom.2009.03.007.
33. Muñoz-Jordán JL, Laurent-Rolle M, Martínez-Sobrido L, Ashok M, Ian W, Mun JL. Inhibition of alpha/beta interferon signaling by the NS4b protein of Flaviviruses. Journal of Virology 2005. DOI:10.1128/JVI.79.13.8004.
34. Welsch S, Miller S, Romero-Brey I, et al. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. [Internet]. Cell Host & Microbe 2009; 5: 365-375.
35. Umareddy I, Chao A, Sampath A, Gu F, Vasudevan SG. Dengue virus NS4b interacts with NS3 and dissociates it from single-stranded RNA. [Internet]. Journal of General Virology 2012; 895: 39-56; Doi: 10.1007/978-1-61779-882-5_3
36. Westaway EG, Khromykh AA, Kenney MT, Mackenzie JM, Jones MK. Proteins C and NS4b of the flavivirus Kunjin translocate independently into the nucleus. [Internet]. Virology 1997; 234: 31-41.
37. Youn S, Li T, McCune BT, et al. Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus. [Internet]. Journal of Virology 2012; 86: 7360-7371.
38. Yu L, Takeda K, Markoff L. Protein-protein interactions among West Nile non-structural proteins and transmembrane complex formation in mammalian cells [Internet]. Virology 2013; 446: 365-377.
39. Zou J, Lee LT, Wang QY, et al. Mapping the interactions between the NS4b and NS3 proteins of dengue virus. [Internet]. Journal of Virology 2015. DOI:10.1128/JVI.03454-14.
40. Zou J, Xie X, Wang Q-Y, et al. Characterization of dengue virus NS4a and NS4b protein interaction. [Internet]. Journal of Virology 2015. DOI:10.1128/JVI.03453-14.
41. Li X-D, Ye H-Q, Deng C-L, et al. Genetic interaction between NS4a and NS4b for replication of Japanese encephalitis virus. [Internet]. Journal of General Virology 2015. DOI:10.1099/vir.0.000044.
42. Zou J, Xie X, Lee LT, et al. Dimerization of Flavivirus NS4b protein. [Internet]. Journal of Virology 2014. DOI:10.1128/JVI.02782-13.
43. Khromykh AA, Sedlak PL, Guyatt KJ, Hall RA, Westaway EG. Efficient trans-complementation of the flavivirus Kunjin NS5 protein but not of the NS1 protein requires its coexpression with other components of the viral replicase. Journal of Virology 1999; 73: 10272-10280.
44. Khan AM, Heiny AT, Lee KX, et al. Large-scale analysis of antigenic diversity of T-cell epitopes in dengue virus. [Internet]. BMC Bioinformatics 2006; 7(Suppl 5): S4.
45. Zou G, Xu HY, Qing M, Wang Q-Y, Shi P-Y. Development and characterization of a stable luciferase dengue virus for high-throughput screening. [Internet]. Antiviral Research 2011; 91: 11-19.
46. Hanley KA, Manlucu LR, Gilmore LE, et al. A trade-off in replication in mosquito versus mammalian systems conferred by a point mutation in the NS4B protein of dengue virus type 4. [Internet]. Virology 2003; 312: 222-232.
47. Blaney J. Mutations which enhance the replication of dengue virus type 4 and an antigenic chimeric dengue virus type 2/4 vaccine candidate in Vero cells. [Internet]. Vaccine 2003; 21: 4317-4327.
48. Pletnev AG, Putnak R, Speicher J, Wagar EJ, Vaughn DW. West Nile virus/dengue type 4 virus chimeras that are reduced in neurovirulence and peripheral virulence without loss of immunogenicity or protective efficacy. [Internet]. Proceedings of the National Academy of Sciences of the United States of America 2002; 99: 3036-3041.
49. Grant D, Tan GK, Qing M, et al. A single amino acid in nonstructural protein NS4B confers virulence to dengue virus in AG129 mice through enhancement of viral RNA synthesis. [Internet]. Journal of Virology 2011; 85: 7775-7787.
50. Orozco S, Schmid MA, Parameswaran P, et al. Characterization of a model of lethal dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor. [Internet]. Journal of General Virology 2012; 93: 2152-2157.
51. Beasley DWC, Morin M, Lamb AR, et al. Adaptation of yellow fever virus 17D to Vero cells is associated with mutations in structural and non-structural protein genes. [Internet]. Virus Research 2013; 176: 280-284.
52. Mcarthur MA, Suderman MT, Xiao S, Barrett ADT, Mutebi J. Molecular characterization of a hamster viscerotropic strain of yellow fever virus. Journal of Virology 2003; 77: 1462-1468.
53. Dunster LM, Wang H, Ryman KD, et al. Molecular and biological changes associated with HeLa cell attenuation of wild-type yellow fever virus. [Internet]. Virology 1999; 261: 309-318.
54. Moulin J-C, Silvano J, Barban V, Riou P, Allain C. Yellow fever vaccine: comparison of the neurovirulence of new 17D-204 Stamaril™ seed lots and RK 168-73 strain. [Internet]. Biologicals 2013; 41: 238-246.
55. Charlier N, Molenkamp R, Leyssen P, et al. Exchanging the yellow fever virus envelope proteins with Modoc virus prM and E proteins results in a chimeric virus that is neuroinvasive in SCID mice. Journal of Virology 2004; 1462-1468 DOI:10.1128/JVI.78.14.7418.
56. Wicker JA, Whiteman MC, Beasley DWC, et al. A single amino acid substitution in the central portion of the West Nile virus NS4B protein confers a highly attenuated phenotype in mice. [Internet]. Virology 2006; 349: 245-253.
57. Wicker JA, Whiteman MC, Beasley DWC, et al. Mutational analysis of the West Nile virus NS4B protein. [Internet]. Virology 2012; 426: 22-33.
58. Puig-Basagoiti F, Tilgner M, Bennett CJ, et al. A mouse cell-adapted NS4B mutation attenuates West Nile virus RNA synthesis. [Internet]. Virology 2007; 361: 229-241.
59. Ni H, Chang GJ, Xie H, Trent DW, Barrett AD. Molecular basis of attenuation of neurovirulence of wild-type Japanese encephalitis virus strain SA14. [Internet]. Journal of General Virology 1995; 76(Pt 2): 409-413.
60. Le Breton M, Meyniel-Schicklin L, Deloire A, et al. Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen. [Internet]. BMC Microbiology 2011; 11: 234.
61. Khadka S, Vangeloff AD, Zhang C, et al. A physical interaction network of dengue virus and human proteins. [Internet]. Molecular and Cellular Proteomics 2011; 10: M111.012187.
62. Krishnan MN, Ng A, Sukumaran B, et al. RNA interference screen for human genes associated with West Nile virus infection. [Internet]. Nature 2008; 455: 242-245.
63. Ma-Lauer Y, Lei J, Hilgenfeld R, von Brunn A. Virus-host interactomes-antiviral drug discovery. [Internet]. Current Opinion in Virology 2012; 2: 614-621.
64. Wang RY-L, Nagy PD. Tomato bushy stunt virus co-opts the RNA-binding function of a host metabolic enzyme for viral genomic RNA synthesis. [Internet]. Cell Host & Microbe 2008; 3: 178-187.
65. Mairiang D, Zhang H, Sodja A, et al. Identification of new protein interactions between dengue fever virus and its hosts, human and mosquito. [Internet]. PLoS ONE 2013; 8: e53535.
66. Gareau JR, Lima CD. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. [Internet]. Nature Reviews Molecular Cell Biology 2010; 11: 861-871.
67. Chiu M-W, Shih H-M, Yang T-H, Yang Y-L. The type 2 dengue virus envelope protein interacts with small ubiquitin-like modifier-1 (SUMO-1) conjugating enzyme 9 (Ubc9). [Internet]. Journal of Biomedical Science 2007; 14: 429-444.
68. Wilson VG. Sumoylation at the host-pathogen interface [Internet]. Biomolecules 2012; 2: 203-227.
69. Varadaraj A, Mattoscio D, Chiocca S. SUMO Ubc9 enzyme as a viral target. [Internet]. IUBMB Life 2014. DOI:10.1002/iub.1240.
70. Nevels M, Brune W, Shenk T. SUMOylation of the human cytomegalovirus 72-kilodalton IE1 protein facilitates expression of the 86-kilodalton IE2 protein and promotes viral replication. [Internet]. Journal of Virology 2004; 78: 7803-7812.
71. Cuchet-Lourenço D, Vanni E, Glass M, Orr A, Everett RD. Herpes simplex virus 1 ubiquitin ligase ICP0 interacts with PML isoform I and induces its SUMO-independent degradation. [Internet]. Journal of Virology 2012; 86: 11209-11222.
72. Colombo R, Boggio R, Seiser C, Draetta GF, Chiocca S. The adenovirus protein Gam1 interferes with sumoylation of histone deacetylase 1. [Internet]. EMBO Reports 2002; 3: 1062-1068.
73. Basler CF, Wang X, Mühlberger E, et al. The Ebola virus VP35 protein functions as a type I IFN antagonist. [Internet]. Proceedings of the National Academy of Sciences of the United States of America 2000; 97: 12289-12294.
74. Chen S-C, Chang L-Y, Wang Y-W, et al. Sumoylation-promoted enterovirus 71 3C degradation correlates with a reduction in viral replication and cell apoptosis. [Internet]. Journal of Biological Chemistry 2011; 286: 31373-3137384.
75. Alshareeda AT, Negm OH, Green AR, et al. SUMOylation proteins in breast cancer. [Internet]. Breast Cancer Research and Treatment 2014; 144: 519-530.
76. Hoeller D, Dikic I. Targeting the ubiquitin system in cancer therapy. [Internet]. Nature 2009; 458: 438-444.
77. Gerace L. Nuclear export signals and the fast track to the cytoplasm minireview. Cell 1995; 82: 341-344.
78. Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. [Internet]. Nature 2009; 461: 788-92.
79. Aguirre S, Maestre AM, Pagni S, et al. DENV inhibits type I IFN production in infected cells by cleaving human STING. [Internet]. PLoS Pathogen 2012; 8: e1002934.
80. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. [Internet]. Annual Review of Immunology 2014; 32: 513-545.
81. Schoggins JW, Wilson SJ, Panis M, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. [Internet]. Nature 2011; 472: 481-485.
82. Mun JL. Subversion of Interferon by Dengue Virus. 2010; 338: 35-44.
83. Muñoz-Jordan JL, Sánchez-Burgos GG, Laurent-Rolle M, García-Sastre A. Inhibition of interferon signaling by dengue virus. [Internet]. Proceedings of the National Academy of Sciences of the United States of America 2003; 100: 14333-14338.
84. Evans JD, Seeger C. Differential effects of mutations in NS4B on West Nile virus replication and inhibition of interferon signaling. [Internet]. Journal of Virology 2007; 81: 11809-11816.
85. Umareddy I, Tang KF, Vasudevan SG, Devi S, Hibberd ML, Gu F. Dengue virus regulates type I interferon signalling in a strain-dependent manner in human cell lines. [Internet]. Journal of General Virology 2008; 89: 3052-3062.
86. Green AM, Beatty PR, Hadjilaou A, Harris E. Innate immunity to dengue virus infection and subversion of antiviral responses. [Internet]. Journal of Molecular Biology 2014; 426: 1148-1160.
87. Nemésio H, Palomares-Jerez F, Villalaín J. NS4A and NS4B proteins from dengue virus: membranotropic regions. [Internet]. Biochimica et Biophysica Acta 2012; 1818: 932-941.
88. Yang T-C, Li S-W, Lai C-C, et al. Proteomic analysis for type I interferon antagonism of Japanese encephalitis virus NS5 protein. [Internet]. Proteomics 2013; 13: 3442-3456.
89. Rogers RS, Horvath CM, Matunis MJ. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. [Internet]. Journal of Biological Chemistry 2003; 278: 30091-30097.
90. Liu et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proceedings of the National Academy of Sciences USA 1998; 95: 10626-10631.
91. Droescher M, Begitt A, Marg A, Zacharias M, Vinkemeier U. Cytokine-induced paracrystals prolong the activity of signal transducers and activators of transcription (STAT) and provide a model for the regulation of protein solubility by small ubiquitin-like modifier (SUMO). [Internet]. Journal of Biological Chemistry 2011; 286: 18731-18746.
92. Ding S-W. RNA-based antiviral immunity. [Internet]. Nature Reviews Immunology 2010; 10: 632-644.
93. Pijlman GP. Flavivirus RNAi suppression: decoding non-coding RNA. [Internet]. Current Opinion in Virology 2014; 7C: 55-60.
94. Chen S, Chahar HS, Abraham S, et al. Ago-2-mediated slicer activity is essential for anti-flaviviral efficacy of RNAi. [Internet]. PLoS ONE 2011; 6: e27551.
95. Kakumani PK, Ponia SS, S RK, et al. Role of RNA Interference (RNAi) in dengue virus replication and identification of NS4b as an RNAi suppressor. [Internet]. Journal of Virology 2013; 87: 8870-8883.
96. Omarov RT, Scholthof HB. Antiviral resistance in plants. [Internet]. Methods Mol Biol 2012; 894: 39-56.
97. Cleef KWR Van, Mierlo JT Van, Beek M Van Den, Rij RP Van. Identification of viral suppressors of RNAi by a reporter assay in Drosophila S2 cell culture. Methods Mol Biol 2011; 721: DOI:10.1007/978-1-61779-037-9_12.
98. Reineke LC, Lloyd RE. Diversion of stress granules and P-bodies during viral infection. [Internet]. Virology 2013; 436: 255-267.
99. Buchan JR, Parker R. Eukaryotic stress granules: the ins and out of translation. Molecular Cell 2009; 36: 932-941.
100. Lloyd RE. How do viruses interact with stress-associated RNA granules? [Internet]. PLoS Pathogen 2012; 8: e1002741.
101. Courtney SC, Scherbik SV, Stockman BM, Brinton MA. West Nile virus infections suppress early viral RNA synthesis and avoid inducing the cell stress granule response. [Internet]. Journal of Virology 2012; 86: 3647-3657.
102. Blázquez A-B, Escribano-Romero E, Merino-Ramos T, Saiz J-C, Martín-Acebes MA. Stress responses in flavivirus-infected cells: activation of unfolded protein response and autophagy. [Internet]. Frontiers in Microbiology 2014; 5: 266.
103. Smith JA. A new paradigm: innate immune sensing of viruses via the unfolded protein response. [Internet]. Frontiers in Microbiology 2014; 5: 222.
104. Yu C-Y, Hsu Y-W, Liao C-L, Lin Y-L. Flavivirus infection activates the XBP1 pathway of the unfolded protein response to cope with endoplasmic reticulum stress. [Internet]. Journal of Virology 2006; 80: 11868-11880.
105. Lee A-H, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. [Internet]. Molecular Cell. Biology 2003; 23: 7448-7459.
106. Ambrose RL, Mackenzie JM. West Nile virus differentially modulates the unfolded protein response to facilitate replication and immune evasion. [Internet]. Journal of Virology 2011; 85: 2723-2732.
107. Peña J, Harris E. Dengue virus modulates the unfolded protein response in a time-dependent manner. [Internet]. Journal of Biological Chemistry 2011; 286: 14226-14236.
108. Courageot M, Frenkiel M, Dos Santos D, et al. α-Glucosidase inhibitors reduce dengue virus production by affecting the initial steps of virion morphogenesis in the endoplasmic reticulum. Journal of Virology 2000. DOI:10.1128/JVI.74.1.564-572.2000.
109. Whitby K, Pierson TC, Geiss B, et al. Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. Journal of Virology 2005. DOI:10.1128/JVI.79.14.8698.
110. Wu S, Lee C, Liao C, et al. Antiviral effects of an iminosugar derivative on flavivirus infections. Journal of Virology 2002; 76: 3596-3604.
111. Schul W, Liu W, Xu H-Y, Flamand M, Vasudevan SG. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. [Internet]. Journal of Infectious Diseases 2007; 195: 665-674.
112. Chang J, Schul W, Butters TD, et al. Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. [Internet]. Antiviral Research 2011; 89: 26-34.
113. Chang J, Wang L, Ma D, et al. Novel imino sugar derivatives demonstrate potent antiviral activity against flaviviruses. [Internet]. Antimicrobial Agents and Chemotherapy 2009; 53: 1501-1508.
114. Fraser JE, Watanabe S, Wang C, et al. A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection. [Internet]. Journal of Infectious Diseases 2014; 210: 1780-1791.
115. Low JSY, Wu KX, Chen KC, Ng MM-L, Chu JJH. Narasin, a novel antiviral compound that blocks dengue virus protein expression. [Internet]. Antiviral Therapy 2011; 16: 1203-1218.
116. Patkar CG, Larsen M, Owston M, Smith JL, Kuhn RJ. Identification of inhibitors of yellow fever virus replication using a replicon-based high-throughput assay. [Internet]. Antimicrobial Agents and Chemotherapy 2009; 53: 4103-4114.
117. Van Cleef KWR, Overheul GJ, Thomassen MC, et al. Identification of a new dengue virus inhibitor that targets the viral NS4B protein and restricts genomic RNA replication. [Internet]. Antiviral Research 2013; 99: 165-171.
118. Choi M, Lee S, Choi T, Lee C. A hepatitis C virus NS4B inhibitor suppresses viral genome replication by disrupting NS4B's dimerization/multimerization as well as its interaction with NS5A. [Internet]. Virus Genes 2013; 47: 395-407.
119. De Wispelaere M, LaCroix AJ, Yang PL. The small molecules AZD0530 and dasatinib inhibit dengue virus RNA replication via Fyn kinase. [Internet]. Journal of Virology 2013; 87: 7367-7381.
120. Gouttenoire J, Penin F, Moradpour D. Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory. Reviews in Medicinal DOI:10.1002/rmv.640.
121. Gouttenoire J, Castet V, Montserret R, et al. Identification of a novel determinant for membrane association in hepatitis C virus nonstructural protein 4B. Journal of Virology 2009; 83: 6257-6268.
122. Yu G-Y, Lee K-J, Gao L, Lai MMC. Palmitoylation and polymerization of hepatitis C virus NS4B protein. [Internet]. Journal of Virology 2006; 80: 6013-6023.
123. Einav S, Elazar M, Danieli T, Jeffrey S, Glenn JS. A nucleotide binding motif in hepatitis C virus (HCV) NS4B mediates HCV RNA replication. Journal of Virology 2004. DOI:10.1128/JVI.78.20.11288.
124. Thompson A. Biochemical characterization of recombinant hepatitis C virus nonstructural protein 4B: evidence for ATP/GTP hydrolysis and adenylate kinase activity. Biotechniques 2005; 38: 511-511.
125. Han Q, Manna D, Belton K, Cole R, Konan KV. Modulation of hepatitis C virus genome encapsidation by nonstructural protein 4B. [Internet]. Journal of Virology 2013; 87: 7409-7422.
126. Melén K, Fagerlund R, Nyqvist M, Keskinen P, Julkunen I. Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. [Internet]. Journal of Medical Virology 2004; 73: 536-547.
127. Li S, Ye L, Yu X, et al. Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-κB activation. [Internet]. Virology 2009; 391: 257-264.
128. Einav S, Sobol HD, Gehrig E, Glenn JS. The hepatitis C virus (HCV) NS4B RNA binding inhibitor clemizole is highly synergistic with HCV protease inhibitors. [Internet]. Journal of Infectious Diseases 2010; 202: 65-74.
129. Kohler JJ, Nettles JH, Hurwitz SJ, Bassit L, Stanton RA. Approaches to hepatitis C treatment and cure using NS5A inhibitors. Infection and Drug Resistance 2014; 7: 41-56. http://www.dx.doi.org/10.2147/IDR.S36247130
130. Moradpour D, Penin F. Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol 2013; 369: 113-142. DOI:10.1007/978-3-642-27340-7_5.131.