The dengue virus NS5 protein as a target for drug discovery

Antiviral Research

Volumn 119, Issue , 2015, Pages 57-67

  Lim, Siew Pheng ^a   Noble, Christian G ^a   Shi, Pei Yong ^a  

^a NOVARTIS INSTITUTE FOR TROPICAL DISEASES   (Singapore)

Author keywords

Antiviral; Dengue hemorrhagic fever; Dengue virus; Methyltransferase; NS5 protein; RNA polymerase

Indexed keywords

ANTIVIRUS AGENT; CAPPED RNA; GUANOSINE TRIPHOSPHATE; METHYLTRANSFERASE; METHYLTRANSFERASE INHIBITOR; NONSTRUCTURAL PROTEIN 5; RNA DIRECTED RNA POLYMERASE; RNA DIRECTED RNA POLYMERASE INHIBITOR; VIRUS RNA; ENZYME INHIBITOR; NS5 PROTEIN, DENGUE VIRUS; VIRAL PROTEIN;

CAPPING PHENOMENON; CATALYSIS; CRYSTAL STRUCTURE; DENGUE VIRUS; DENGUE VIRUS 3; ENZYME ACTIVITY; HUMAN; HYDROLYSIS; LIGAND BINDING; MUTAGENESIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; RNA BINDING; RNA STRUCTURE; RNA SYNTHESIS; SITE DIRECTED MUTAGENESIS; VIRUS REPLICATION; X RAY CRYSTALLOGRAPHY; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; GENETICS; METABOLISM; PROSPECTIVE STUDY; PROTEIN TERTIARY STRUCTURE; SEVERE DENGUE;

DENGUE VIRUS; FLAVIVIRUS;

ANTIVIRAL AGENTS; DENGUE VIRUS; DRUG DISCOVERY; ENZYME INHIBITORS; METHYLTRANSFERASES; PROSPECTIVE STUDIES; PROTEIN STRUCTURE, TERTIARY; RNA REPLICASE; RNA, VIRAL; SEVERE DENGUE; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84928889480     PISSN: 01663542     EISSN: 18729096     Source Type: Journal    
DOI: 10.1016/j.antiviral.2015.04.010     Document Type: Review

References (106)

1. M. Ackermann, and R. Padmanabhan De novo synthesis of RNA by the dengue virus RNA-dependent RNA polymerase exhibits temperature dependence at the initiation but not elongation phase J. Biol. Chem 276 2001 39926 39937
2. R. Assenberg, J. Ren, A. Verma, T.S. Walter, D. Alderton, R.J. Hurrelbrink, S.D. Fuller, S. Bressanelli, R.J. Owens, D.I. Stuart, and J.M. Grimes Crystal structure of the Murray Valley encephalitis virus NS5 methyltransferase domain in complex with cap analogues J. Gen. Virol. 88 2007 2228 2236
3. K. Barral, C. Sallamand, C. Petzold, B. Coutard, A. Collet, Y. Thillier, J. Zimmermann, J.J. Vasseur, B. Canard, J. Rohayem, F. Debart, and E. Decroly Development of specific dengue virus 2′-O- and N7-methyltransferase assays for antiviral drug screening Antiviral Res. 99 2013 292 300
4. K.J. Blight, A.A. Kolykhalov, and C.M. Rice Efficient initiation of HCV RNA replication in cell culture Science 290 5498 2000 1972 1974
5. M. Bollati, M. Milani, E. Mastrangelo, S. Ricagno, G. Tedeschi, S. Nonnis, E. Decroly, B. Selisko, X de L, B. Coutard, B. Canard, and M. Bolognesi Recognition of RNA cap in the Wesselsbron virus NS5 methyltransferase domain: implications for RNA-capping mechanisms in Flavivirus J. Mol. Biol. 385 2009 140 152
6. M. Bollati, K. Alvarez, R. Assenberg, C. Baronti, B. Canard, S. Cook, B. Coutard, E. Decroly, X. de Lamballerie, E.A. Gould, G. Grard, J.M. Grimes, R. Hilgenfeld, A.M. Jansson, H. Malet, E.J. Mancini, E. Mastrangelo, A. Mattevi, M. Milani, G. Moureau, J. Neyts, R.J. Owens, J. Ren, B. Selisko, S. Speroni, H. Steuber, D.I. Stuart, T. Unge, and M. Bolognesi Structure and functionality in flavivirus NS-proteins: perspectives for drug design Antiviral Res. 87 2010 125 148
7. M.B. Brecher, Z. Li, J. Zhang, H. Chen, Q. Lin, B. Liu, and H. Li Refolding of a fully functional flavivirus methyltransferase revealed that S-adenosyl methionine but not S-adenosyl homocysteine is copurified with flavivirus methyltransferase Protein Sci. 24 2014 117 128
8. S. Bressanelli, L. Tomei, A. Roussel, I. Incitti, R.L. Vitale, M. Mathieu, R. De Francesco, and F.A. Rey Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus Proc. Natl. Acad. Sci. U.S.A. 96 1999 13034 13039
9. S. Bressanelli, L. Tomei, F.A. Rey, and R. De Francesco Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides J. Virol. 76 2002 3482 3492
10. A.J. Brooks, M. Johansson, A.V. John, Y. Xu, D.A. Jans, and S.G. Vasudevan The interdomain region of dengue NS5 protein that binds to the viral helicase NS3 contains independently functional importin beta 1 and importin alpha/beta-recognized nuclear localization signals J. Biol. Chem. 277 39 2002 36399 36407
11. C. Bussetta, and K.H. Choi Dengue virus nonstructural protein 5 adopts multiple conformations in solution Biochemistry 51 2012 5921 5931
12. C. Caillet-Saguy, S.P. Lim, P.-Y. Shi, J. Lescar, and S. Bressanelli Polymerases of hepatitis C viruses and flaviviruses: structural and mechanistic insights and drug development Antiviral Res. 105 2014 8 16
13. J. Cardosa, M.H. Ooi, P.H. Tio, D. Perera, E.C. Holmes, K. Bibi, and Z. Abdul Manap Dengue virus serotype 2 from a sylvatic lineage isolated from a patient with dengue hemorrhagic fever PLoS Negl. Trop. Dis. 3 2009 e423
14. M. Carocci, S.M. Hinshaw, M.A. Rodgers, V.A. Villareal, D.J. Burri, R. Pilankatta, N.P. Maharaj, M.U. Gack, E.J. Stavale, K.L. Warfield, and P.L. Yang The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication Antimicrob. Agents Chemother. 59 1 2015 85 95
15. C. Castro, E.D. Smidansky, J.J. Arnold, K.R. Maksimchuk, I. Moustafa, A. Uchida, M. Götte, W. Konigsberg, and C.E. Cameron Nucleic acid polymerases use a general acid for nucleotidyl transfer Nat. Struct. Mol. Biol. 16 2 2009 212 218
16. Y.L. Chen, G.N. Abdul, R. Karuna, Y. Fu, S.P. Lim, W. Schul, F. Gu, M. Herve, F. Yokohama, G. Wang, D. Cerny, K. Fink, F. Blasco, and P.-Y. Shi Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir J. Virol. 88 3 2014 1740 1747
17. K.Y. Chung, H. Dong, A.T. Chao, P.-Y. Shi, J. Lescar, and S.P. Lim Higher catalytic efficiency of N-7-methylation is responsible for processive N-7 and 2′-O methyltransferase activity in dengue virus Virology 402 2010 52 60
18. T. Cihlar, and A.S. Ray Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine Antiviral Res. 85 2010 39 58
19. B. Coutard, E. Decroly, C. Li, A. Sharff, J. Lescar, G. Bricogne, and K. Barral Assessment of Dengue virus helicase and methyltransferase as targets for fragment-based drug discovery Antiviral Res. 106 2014 61 70
20. S. Daffis, K.J. Szretter, J. Schriewer, J. Li, S. Youn, J. Errett, T.Y. Lin, S. Schneller, R. Zust, H. Dong, V. Thiel, G.C. Sen, V. Fensterl, W.B. Klimstra, T.C. Pierson, R.M. Buller, M. Gale Jr., P.Y. Shi, and M.S. Diamond 2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members Nature 468 2010 452 456
21. A.D. Davidson Chapter 2. New insights into flavivirus nonstructural protein 5 Adv. Virus Res. 74 2009 41 101
22. E. De Clercq A 40-year journey in search of selective antiviral chemotherapy Annu. Rev. Pharmacol. Toxicol. 51 2011 1 24
23. K. Donadello, S. Cristallini, F.S. Taccone, S. Lorent, J.L. Vincent, D. de Backer, and F. Jacobs Strongyloides disseminated infection successfully treated with parenteral ivermectin: case report with drug concentration measurements and review of the literature Int. J. Antimicrob. Agents 42 6 2013 580 583
24. H. Dong, D. Ray, S. Ren, B. Zhang, F. Puig-Basagoiti, Y. Takagi, C.K. Ho, H. Li, and P.Y. Shi Distinct RNA elements confer specificity to flavivirus RNA cap methylation events J. Virol. 81 2007 4412 4421
25. H. Dong, S. Ren, B. Zhang, Y. Zhou, F. Puig-Basagoiti, H. Li, and P.Y. Shi West Nile virus methyltransferase catalyzes two methylations of the viral RNA cap through a substrate-repositioning mechanism J. Virol. 82 2008 4295 4307
26. H. Dong, D.C. Chang, X. Xie, Y.X. Toh, K.Y. Chung, G. Zou, J. Lescar, S.P. Lim, and P.Y. Shi Biochemical and genetic characterization of dengue virus methyltransferase Virology 405 2010 568 578
27. H. Dong, L. Liu, G. Zou, Y. Zhao, Z. Li, S.P. Lim, P.Y. Shi, and H. Li Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase J. Biol. Chem. 285 2010 32586 32595
28. H. Dong, D.C. Chang, M.H. Hua, S.P. Lim, Y.H. Chionh, F. Hia, Y.H. Lee, P. Kukkaro, S.M. Lok, P.C. Dedon, and P.Y. Shi 2′-O methylation of internal adenosine by flavivirus NS5 methyltransferase PLoS Pathog. 8 2012 e1002642
29. H. Dong, K. Fink, R. Züst, S.P. Lim, C.F. Qin, and P.Y. Shi Flavivirus RNA methylation J. Gen. Virol. 95 Pt 4 2014 763 778
30. M.P. Egloff, D. Benarroch, B. Selisko, J.L. Romette, and B. Canard An RNA cap (nucleoside-2′-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization EMBO J. 21 2002 2757 2768
31. M.P. Egloff, E. Decroly, H. Malet, B. Selisko, D. Benarroch, F. Ferron, and B. Canard Structural and functional analysis of methylation and 5′-RNA sequence requirements of short capped RNAs by the methyltransferase domain of dengue virus NS5 J. Mol. Biol. 372 2007 723 736
32. S.P. Falk, and B. Weisblum Aptamer displacement screen for flaviviral RNA methyltransferase inhibitors J. Biomol. Screen. 19 2014 1147 1153
33. C.V. Filomatori, N.G. Iglesias, S.M. Villordo, D.E. Alvarez, and A.V. Gamarnik RNA sequences and structures required for the recruitment and activity of the dengue virus polymerase J. Biol. Chem. 286 9 2011 6929 6939
34. D. Fink, and A. Porras Pharmacokinetics of ivermectin in animals and humans W. Campbell, Ivermectin and Abamectin 1989 Springer-Verlag New York, NY 113 130
35. L. Franco, G. Palacios, J.A. Martinez, A. Vázquez, N. Savji, F. De Ory, M.P. Sanchez-Seco, D. Martín, W.I. Lipkin, and A. Tenorio First report of sylvatic DENV-2-associated dengue hemorrhagic fever in West Africa PLoS Negl. Trop. Dis. 8 2011 e1251
36. J.E. Fraser, S. Watanabe, C. Wang, W.K. Chan, B. Maher, A. Lopez-Denman, C. Hick, K.M. Wagstaff, J.M. Mackenzie, P.M. Sexton, S.G. Vasudevan, and D.A. Jans A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection J. Infect. Dis. 210 11 2014 1780 1791
37. L.G. Gebhard, C.V. Filomatori, and A.V. Gamarnik Functional RNA elements in the dengue virus genome Viruses 3 9 2011 1739 1756
38. B.J. Geiss, A.A. Thompson, A.J. Andrews, R.L. Sons, H.H. Gari, S.M. Keenan, and O.B. Peersen Analysis of flavivirus NS5 methyltransferase cap binding J. Mol. Biol. 385 2009 1643 1654
39. B.J. Geiss, H.J. Stahla-Beek, A.M. Hannah, H.H. Gari, B.R. Henderson, B.J. Saeedi, and S.M. Keenan A high-throughput screening assay for the identification of flavivirus NS5 capping enzyme GTP-binding inhibitors: implications for antiviral drug development J. Biomol. Screen. 16 2011 852 861
40. C.S. Hahn, Y.S. Hahn, C.M. Rice, E. Lee, L. Dalgarno, E.G. Strauss, and J.H. Strauss Conserved elements in the 3′ untranslated region of flavivirus RNAs and potential cyclization sequences J. Mol. Biol. 198 1 1987 33 41
41. H. Hannemann, P.Y. Sung, H.C. Chiu, A. Yousuf, J. Bird, S.P. Lim, and A.D. Davidson Serotype-specific differences in dengue virus non-structural protein 5 nuclear localization J. Biol. Chem. 288 31 2013 22621 22635
42. B.R. Henderson, B.J. Saeedi, G. Campagnola, and B.J. Geiss Analysis of RNA binding by the dengue virus NS5 RNA capping enzyme PLoS ONE 6 2011 e25795
43. N.G. Iglesias, C.V. Filomatori, and A.V. Gamarnik The F1 motif of dengue virus polymerase NS5 is involved in promoter-dependent RNA synthesis J. Virol. 85 12 2011 5745 5756
44. M. Issur, B.J. Geiss, I. Bougie, F. Picard-Jean, S. Despins, J. Mayette, S.E. Hobdey, and M. Bisaillon The flavivirus NS5 protein is a true RNA guanylyltransferase that catalyzes a two-step reaction to form the RNA cap structure RNA 15 2009 2340 2350
45. A.M. Jansson, E. Jakobsson, P. Johansson, V. Lantez, B. Coutard, X. de L., T. Unge, and T.A. Jones Structure of the methyltransferase domain from the Modoc virus, a flavivirus with no known vector Acta Crystallogr. D Biol. Crystallogr. 65 2009 796 803
46. E.V. Koonin The phylogeny of RNA-dependent RNA polymerases of positive-strand RNA viruses J. Gen. Virol. 72 1991 2197 2206
47. E.V. Koonin Computer-assisted identification of a putative methyltransferase domain in NS5 protein of flaviviruses and lambda 2 protein of reovirus J. Gen. Virol. 74 1993 733 740
48. A. Kumar, S. Bühler, B. Selisko, A. Davidson, K. Mulder, B. Canard, S. Miller, and R. Bartenschlager Nuclear localization of dengue virus nonstructural protein 5 does not strictly correlate with efficient viral RNA replication and inhibition of type I interferon signaling J. Virol. 87 8 2013 4545 4557
49. C.A. Lesburg, M.B. Cable, E. Ferrari, Z. Hong, A.F. Mannarino, and P.C. Weber Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site Nat. Struct. Biol. 6 10 1999 937 943
50. S.H. Li, H. Dong, X.F. Li, X. Xie, H. Zhao, Y.Q. Deng, X.Y. Wang, Q. Ye, S.Y. Zhu, H.J. Wang, B. Zhang, Q.B. Leng, R. Zuest, E.D. Qin, C.F. Qin, and P.Y. Shi Rational design of a flavivirus vaccine by abolishing viral RNA 2′-O methylation J. Virol. 87 10 2013 5812 5819
51. S.P. Lim, D. Wen, T.L. Yap, C.K. Yan, J. Lescar, and S.G. Vasudevan A scintillation proximity assay for dengue virus NS5 2'-O-methyltransferase-kinetic and inhibition analyses Antiviral Res. 80 2008 360 369
52. S.P. Lim, L.S. Sonntag, C. Noble, S.H. Nilar, R.H. Ng, G. Zou, P. Monaghan, K.Y. Chung, H. Dong, B. Liu, C. Bodenreider, G. Lee, M. Ding, W.L. Chan, G. Wang, Y.L. Jian, A.T. Chao, J. Lescar, Z. Yin, T.R. Vedananda, T.H. Keller, and P.Y. Shi Small molecule inhibitors that selectively block dengue virus methyltransferase J. Biol. Chem. 286 2011 6233 6240
53. S.P. Lim, J.H. Koh, C.C. She, C.W. Liew, A.D. Davidson, L.S. Chua, R. Chandrasekaran, T.C. Cornvik, P.Y. Shi, and J. Lescar A crystal structure of the dengue virus non-structural protein 5 (NS5) polymerase delineates interdomain amino acid residues that enhance its thermostability and de novo initiation activities J. Biol. Chem. 288 43 2013 31105 31114
54. S.P. Lim, Q.Y. Wang, C.G. Noble, Y.L. Chen, H. Dong, B. Zou, F. Yokokawa, S. Nilar, P. Smith, D. Beer, J. Lescar, and P.Y. Shi Ten years of dengue drug discovery: progress and prospects Antiviral Res. 100 2 2013 500 519
55. S.P. Lim, C. Bodenreider, and P.Y. Shi Detection and quantification of flavivirus NS5 methyl-transferase activities Methods Mol. Biol. 1030 2013 249 268
56. V. Lohmann, F. Körner, U. Herian, and R. Bartenschlager Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity J. Virol. 71 11 1997 8416 8428
57. V. Lohmann, F. Körner, J. Koch, U. Herian, L. Theilmann, and R. Bartenschlager Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line Science 285 5424 1999 110 113
58. G. Lu, and P. Gong Crystal Structure of the full-length Japanese encephalitis virus NS5 reveals a conserved methyltransferase-polymerase interface PLoS Pathog. 9 8 2013 e1003549
59. H. Malet, M.P. Egloff, B. Selisko, R.E. Butcher, P.J. Wright, M. Roberts, A. Gruez, G. Sulzenbacher, C. Vonrhein, G. Bricogne, J.M. Mackenzie, A.A. Khromykh, A.D. Davidson, and B. Canard Crystal structure of the RNA polymerase domain of the West Nile virus non-structural protein 5 J. Biol. Chem. 282 2007 10678 10689
60. E. Mastrangelo, M. Bollati, M. Milani, B. Selisko, F. Peyrane, B. Canard, G. Grard, X. de Lamballerie, and M. Bolognesi Structural bases for substrate recognition and activity in Meaban virus nucleoside-2'-O-methyltransferase Protein Sci. 16 2007 1133 1145
61. E. Mastrangelo, M. Pezzullo, T. De Burghgraeve, S. Kaptein, B. Pastorino, K. Dallmeier, X. de Lamballerie, J. Neyts, A.M. Hanson, D.N. Frick, M. Bolognesi, and M. Milani Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug J. Antimicrob. Chemother. 67 2012 1884 1894
62. B.J. Maurer, M.H. Kang, J.G. Villablanca, J. Janeba, S. Groshen, K.K. Matthay, P.M. Sondel, J.M. Maris, H.A. Jackson, F. Goodarzian, H. Shimada, S. Czarnecki, B. Hasenauer, C.P. Reynolds, and A. Marachelian Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium Pediatr. Blood Cancer 60 11 2013 1801 1808
63. J. McGrath, and P. Trojer Targeting histone lysine methylation in cancer Pharmacol. Ther. 150 2015 1 22
64. M. Milani, E. Mastrangelo, M. Bollati, B. Selisko, E. Decroly, M. Bouvet, B. Canard, and M. Bolognesi Flaviviral methyltransferase/RNA interaction: structural basis for enzyme inhibition Antiviral Res. 83 2009 28 34
65. N. Mody, and G.D. Mcilroy The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes Biochem. Pharmacol. 91 3 2014 277 286
66. N.M. Nguyen, C.N. Tran, L.K. Phung, K.T. Duong, A. Huynh Hle, J. Farrar, Q.T. Nguyen, H.T. Tran, C.V. Nguyen, L. Merson, L.T. Hoang, M.L. Hibberd, P.P. Aw, A. Wilm, N. Nagarajan, D.T. Nguyen, M.P. Pham, T.T. Nguyen, H. Javanbakht, K. Klumpp, J. Hammond, R. Petric, M. Wolbers, C.T. Nguyen, and C.P. Simmons A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients J. Infect. Dis. 207 2013 1442 1450
67. P. Niyomrattanakit, S.N. Abas, C.C. Lim, D. Beer, P.Y. Shi, and Y.L. Chen A fluorescence-based alkaline phosphatase-coupled polymerase assay for identification of inhibitors of dengue virus RNA-dependent RNA polymerase J. Biomol. Screen. 16 2010 201 210
68. P. Niyomrattanakit, Y.L. Chen, H. Dong, Z. Yin, M. Qing, J.F. Glickman, K. Lin, D. Mueller, H. Voshol, J.Y. Lim, S. Nilar, T.H. Keller, and P.Y. Shi Inhibition of dengue virus polymerase by blocking of the RNA tunnel J. Virol. 84 2010 5678 5686
69. P. Niyomrattanakit, K.F. Wan, K.Y. Chung, S.N. Abas, C.C. She, H.P. Dong, C.C. Lim, A.T. Chao, C.B. Lee, S. Nilar, J. Lescar, P.Y. Shi, D. Beer, and S.P. Lim Stabilization of Dengue virus polymerase in de novo initiation assay provides advantages for compound screening Anti-vir. Res. J. 2015 (accepted)
70. C.G. Noble, and P.Y. Shi Structural biology of dengue virus enzymes: towards rational design of therapeutics Antiviral Res. 96 2 2012 115 126
71. C.G. Noble, S.P. Lim, Y.L. Chen, C.W. Liew, L. Yap, J. Lescar, and P.Y. Shi Conformational flexibility of the Dengue virus RNA-dependent RNA polymerase revealed by a complex with an inhibitor J. Virol. 87 9 2013 5291 5295
72. C.G. Noble, S.H. Li, H. Dong, S.H. Chew, and P.-Y. Shi Crystal structure of dengue virus methyltransferase without S-adenosyl-l-methionine Antiviral Res. 111 2014 78 81
73. D. Normile Tropical medicine. Surprising new dengue virus throws a spanner in disease control efforts Science 342 6157 2013 415
74. P.N. Paradkar, E.E. Ooi, B.J. Hanson, D.J. Gubler, and S.G. Vasudevan Unfolded protein response (UPR) gene expression during antibody-dependent enhanced infection of cultured monocytes correlates with dengue disease severity Biosci. Rep. 31 2011 221 230
75. J. Pena, and E. Harris Dengue virus modulates the unfolded protein response in a time-dependent manner J. Biol. Chem. 286 2011 14226 14236
76. S. Potisopon, S. Priet, A. Collet, E. Decroly, B. Canard, and B. Selisko The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain Nucleic Acids Res. 42 2014 11642 11656
77. M.J. Pryor, S.M. Rawlinson, R.E. Butcher, C.L. Barton, T.A. Waterhouse, S.G. Vasudevan, P.G. Bardin, P.J. Wright, D.A. Jans, and A.D. Davidson Nuclear localization of dengue virus nonstructural protein 5 through its importin alpha/beta recognized nuclear localization sequences is integral to viral infection Traffic 2007 8 2007 795 807
78. S.M. Rawlinson, M.J. Pryor, P.J. Wright, and D.A. Jans CRM1-mediated nuclear export of dengue virus RNA polymerase NS5 modulates interleukin-8 induction and virus production J. Biol. Chem. 284 23 2009 15589 15597
79. D. Ray, A. Shah, M. Tilgner, Y. Guo, Y. Zhao, H. Dong, T.S. Deas, Y. Zhou, H. Li, and P.Y. Shi West Nile virus 5′-cap structure is formed by sequential guanine N-7 and ribose 2′-O methylations by nonstructural protein 5 J. Virol. 80 2006 8362 8370
80. S.L. Rossi, F. Nasar, J. Cardosa, S.V. Mayer, R.B. Tesh, K.A. Hanley, S.C. Weaver, and N. Vasilakis Genetic and phenotypic characterization of sylvatic dengue virus type 4 strains Virology 423 2012 58 67
81. B. Selisko, H. Dutartre, J.C. Guillemot, C. Debarnot, D. Benarroch, A. Khromykh, P. Desprès, M.P. Egloff, and B. Canard Comparative mechanistic studies of de novo RNA synthesis by flavivirus RNA-dependent RNA polymerases Virology 351 1 2006 145 158
82. B. Selisko, F.F. Peyrane, B. Canard, K. Alvarez, and E. Decroly Biochemical characterization of the (nucleoside-2′O)-methyltransferase activity of dengue virus protein NS5 using purified capped RNA oligonucleotides (7Me)GpppAC(n) and GpppAC(n) J. Gen. Virol. 91 2010 112 121
83. B. Selisko, S. Potisopon, R. Agred, S. Priet, I. Varlet, Y. Thillier, C. Sallamand, F. Debart, J.J. Vasseur, and B. Canard Molecular basis for nucleotide conservation at the ends of the dengue virus genome PLoS Pathog. 8 9 2012 e1002912
84. B. Selisko, C. Wang, E. Harris, and B. Canard Regulation of Flavivirus RNA synthesis and replication Curr. Opin. Virol. 9C 2014 74 83
85. T.M. Smith, S.P. Lim, K. Yue, S.A. Busby, R. Arora, C.C. Seh, S.K. Wright, R. Nutiu, P. Niyomrattanakit, K.F. Wan, D. Beer, P.Y. Shi, and T.E. Benson Identifying Initiation and Elongation Inhibitors of Dengue Virus RNA Polymerase in a High-Throughput Lead-Finding Campaign J. Biomol. Screen. 20 1 2014 153 163
86. R. Sousa Structural and mechanistic relationships between nucleic acid polymerases Trends Biochem. Sci. 21 5 1996 186 190
87. H.J. Stahla-Beek, D.G. April, B.J. Saeedi, A.M. Hannah, S.M. Keenan, and B.J. Geiss Identification of a novel antiviral inhibitor of the flavivirus guanylyltransferase enzyme J. Virol. 86 2012 8730 8739
88. T.A. Steitz, S.J. Smerdon, J. Jäger, and C.M. Joyce A unified polymerase mechanism for nonhomologous DNA and RNA polymerases Science 266 5193 1994 2022 2025
89. P. Surana, V. Satchidanandam, and D.T. Nair RNA-dependent RNA polymerase of Japanese encephalitis virus binds the initiator nucleotide GTP to form a mechanistically important pre-initiation state Nucleic Acids Res. 42 4 2009 2758 2773
90. H. Takahashi, C. Takahashi, N.J. Moreland, Y.T. Chang, T. Sawasaki, A. Ryo, S.G. Vasudevan, Y. Suzuki, and N. Yamamoto Establishment of a robust dengue virus NS3-NS5 binding assay for identification of protein-protein interaction inhibitors Antiviral Res. 96 3 2012 305 314
91. C.S. Tan, J.M. Hobson-Peters, M.J. Stoermer, D.P. Fairlie, A.A. Khromykh, and R.A. Hall An interaction between the methyltransferase and RNA dependent RNA polymerase domains of the West Nile virus NS5 protein J. Gen. Virol. 94 Pt 9 2013 1961 1971
92. M.Y. Tay, J.E. Fraser, W.K. Chan, N.J. Moreland, A.P. Rathore, C. Wang, S.G. Vasudevan, and D.A. Jans Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin Antiviral Res. 99 3 2013 301 306
93. M.Y. Tay, W.G. Saw, Y. Zhao, K.W. Chan, D. Singh, Y. Chong, J.K. Forwood, E.E. Ooi, G. Grüber, J. Lescar, D. Luo, and S.G. Vasudevan The C-terminal 50 amino acid residues of Dengue NS3 protein are important for NS3-NS5 interaction and viral replication J. Biol. Chem. 290 4 2015 2379 2394
94. S.M. Tomlinson, and S.J. Watowich Use of parallel validation high-throughput screens to reduce false positives and identify novel dengue NS2B-NS3 protease inhibitors Antiviral Res. 93 2012 245 252
95. I. Umareddy, O. Pluquet, Q.Y. Wang, S.G. Vasudevan, E. Chevet, and F. Gu Dengue virus serotype infection specifies the activation of the unfolded protein response Virol. J. 4 2007 91
96. N. Vasilakis, E.B. Fokam, C.T. Hanson, E. Weinberg, A.A. Sall, S.S. Whitehead, K.A. Hanley, and S.C. Weaver Genetic and phenotypic characterization of sylvatic dengue virus type 2 strains Virology 377 2008 296 307
97. K.M. Wagstaff, S.M. Rawlinson, A.C. Hearps, and D.A. Jans An AlphaScreen®-based assay for high-throughput screening for specific inhibitors of nuclear import J. Biomol. Screen. 16 2 2011 192 200
98. K.M. Wagstaff, H. Sivakumaran, S.M. Heaton, D. Harrich, and D.A. Jans Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus Biochem. J. 443 3 2012 851 856
99. Wl. Yang, J.Y. Lee, and M. Nowotny Making and breaking nucleic acids: two-Mg2+-ion catalysis and substrate specificity Mol. Cell 22 1 2006 5 13
100. T. Yap, T. Xu, Y. Chen, H. Malet, M. Egloff, B. Canard, S. Vasudevan, and J. Lescar Crystal structure of the dengue virus RNA-dependent RNA polymerase catalytic domain at 1.85-angstrom resolution J. Virol. 81 2007 4753 4765
101. L.J. Yap, D. Luo, K.Y. Chung, S.P. Lim, C. Bodenreider, C. Noble, P.Y. Shi, and J. Lescar Crystal structure of the dengue virus methyltransferase bound to a 5′-capped octameric RNA PLoS ONE 5 9 2010
102. Z. Yin, Y.L. Chen, R.R. Kondreddi, W.L. Chan, G. Wang, R.H. Ng, J.Y. Lim, W.Y. Lee, D.A. Jeyaraj, P. Niyomrattanakit, D. Wen, A. Chao, J.F. Glickman, H. Voshol, D. Mueller, C. Spanka, S. Dressler, S. Nilar, S.G. Vasudevan, P.Y. Shi, and T.H. Keller N-sulfonylanthranilic acid derivatives as allosteric inhibitors of dengue viral RNA-dependent RNA polymerase J. Med. Chem. 52 2009 7934 7937
103. Y. Zhao, S. Soh, J. Zheng, K.W.K. Chan, W.W. Phoo, C.C. Lee, M.Y.F. Tay, K. Swaminathan, T.C. Cornvik, S.P. Lim, P. Shi, J. Lescar, S.G. Vasudevan, and D. Luo A crystal structure of the dengue virus NS5 protein reveals a novel inter-domain interface essential for protein flexibility and virus replication PLoS Pathog. 11 3 2015 e1004682
104. Y. Zhou, D. Ray, Y. Zhao, H. Dong, S. Ren, Z. Li, Y. Guo, K. Bernard, P.-Y. Shi, and H. Li Structure and function of flavivirus NS5 methyltransferase J. Virol. 81 2007 3891 3903
105. G. Zou, Y.L. Chen, H. Dong, C.C. Lim, L.J. Yap, Y.H. Yau, S.G. Shochat, J. Lescar, and P.Y. Shi Functional analysis of two cavities in flavivirus NS5 polymerase J. Biol. Chem. 286 2011 14362 14372
106. R. Züst, H. Dong, X.F. Li, D.C. Chang, B. Zhang, T. Balakrishnan, Y.X. Toh, T. Jiang, S.H. Li, Y.Q. Deng, B.R. Ellis, E.M. Ellis, M. Poidinger, F. Zolezzi, C.F. Qin, P.Y. Shi, and K. Fink Rational design of a live attenuated dengue vaccine: 2′-O-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques PLoS Pathog. 9 2013 e1003521