Abstract
Zika virus is considered a major global threat to human kind. Here, we present a crystal structure of one of its essential enzymes, the methyltransferase, with the inhibitor sinefungin. This structure, together with previously solved structures with bound substrates, will provide the information needed for rational inhibitor design. Based on the structural data we suggest the modification of the adenine moiety of sinefungin to increase selectivity and to covalently link it to a GTP analogue, to increase the affinity of the synthesized compounds.
References
Petersen LR, Jamieson DJ, Powers AM, Honein MA (2016) Zika virus. N Engl J Med 374(16):1552–1563. doi:10.1056/NEJMra1602113
Rajah MM, Pardy RD, Condotta SA, Richer MJ, Sagan SM (2016) Zika virus: emergence, phylogenetics, challenges, and opportunities. Acs Infect Dis 2(11):763–772. doi:10.1021/acsinfecdis.6b00161
Barzon L, Trevisan M, Sinigaglia A, Lavezzo E, Palu G (2016) Zika virus: from pathogenesis to disease control. FEMS Microbiol Lett. doi:10.1093/femsle/fnw202
Weaver SC, Costa F, Garcia-Blanco MA, Ko AI, Ribeiro GS, Saade G, Shi PY, Vasilakis N (2016) Zika virus: history, emergence, biology, and prospects for control. Antiviral Res 130:69–80. doi:10.1016/j.antiviral.2016.03.010
Chouin-Carneiro T, Vega-Rua A, Vazeille M, Yebakima A, Girod R, Goindin D, Dupont-Rouzeyrol M, Lourenco-de-Oliveira R, Failloux AB (2016) Differential Susceptibilities of Aedes aegypti and Aedes albopictus from the Americas to Zika Virus. Plos Negl Trop Dis. doi:10.1371/journal.pntd.0004543
Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau V (2015) Potential sexual transmission of zika virus. Emerg Infect Dis 21(2):359–361. doi:10.3201/eid2102.141363
Hills SL, Russell K, Hennessey M, Williams C, Oster AM, Fischer M, Mead P (2016) Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission—Continental United States. Mmwr 65(8):215–216
Fiorentino DG, Montero FJ (2016) The Zika virus and pregnancy. Curr Obstet Gynecol Rep 5(3):234–238. doi:10.1007/s13669-016-0171-1
Schuler-Faccini L, Ribeiro EM, Feitosa IML, Horovitz DDG, Cavalcanti DP, Pessoa A, Doriqui MJR, Neri JI, Neto JMD, Wanderley HYC, Cernach M, El-Husny AS, Pone MVS, Serao CLC, Sanseverino MTV, Brazilian Med Genet Soc Zika E (2016) Possible Association Between Zika Virus Infection and Microcephaly—Brazil, 2015. Mmwr 65(3):59–62
Mlakar J, Korva M, Tul N, Popovic M, Poljsak-Prijatelj M, Mraz J, Kolenc M, Rus KR, Vipotnik TV, Vodusek VF, Vizjak A, Pizem J, Petrovec M, Zupanc TA (2016) Zika virus associated with microcephaly. N Engl J Med 374(10):951–958. doi:10.1056/NEJMoa1600651
Nicastri E, Castilletti C, Liuzzi G, Iannetta M, Capobianchi MR, Ippolito G (2016) Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016. Eurosurveillance 21(32):6–9. doi:10.2807/1560-7917.es.2016.21.32.30314
Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, Dub T, Baudouin L, Teissier A, Larre P, Vial AL, Decam C, Choumet V, Halstead SK, Willison HJ, Musset L, Manuguerra JC, Despres P, Fournier E, Mallet HP, Musso D, Fontanet A, Neil J, Ghawche F (2016) Guillain-Barre syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 387(10027):1531–1539. doi:10.1016/S0140-6736(16)00562-6
Zmurko J, Marques RE, Schols D, Verbeken E, Kaptein SJF, Neyts J (2016) The Viral polymerase inhibitor 7-deaza-2 ‘-C-methyladenosine Is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. PLoS Negl Trop Dis. doi:10.1371/journal.pntd.0004695
Hercík K, Kozak J, Šála M, Dejmek M, Hřebabecký H, Zborníková E, Smola M, Ruzek D, Nencka R, Boura E (2016) Adenosine triphosphate analogs can efficiently inhibit the Zika virus RNA-dependent RNA polymerase. Antiviral Res 137:131–133. doi:10.1016/j.antiviral.2016.11.020
Eyer L, Nencka R, Huvarova I, Palus M, Alves MJ, Gould EA, De Clercq E, Ruzek D (2016) Nucleoside inhibitors of Zika virus. J Infect Dis 214(5):707–711. doi:10.1093/infdis/jiw226
Lei J, Hansen G, Nitsche C, Klein CD, Zhang LL, Hilgenfeld R (2016) Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor. Science 353(6298):503–505. doi:10.1126/science.aag2419
Barrows NJ, Campos RK, Powell ST, Prasanth KR, Schott-Lerner G, Soto-Acosta R, Galarza-Munoz G, McGrath EL, Urrabaz-Garza R, Gao JL, Wu P, Menon R, Saade G, Fernandez-Salas I, Rossi SL, Vasilakis N, Routh A, Bradrick SS, Garcia-Blanco MA (2016) A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe 20(2):259–270. doi:10.1016/j.chom.2016.07.004
Deng YQ, Zhang NN, Li CF, Tian M, Hao JN, Xie XP, Shi PY, Qin CF (2016) Adenosine Analog NITD008 Is a Potent Inhibitor of Zika Virus. Open Forum Infect Dis. doi:10.1093/ofid/ofw175
Kuno G, Chang GJJ (2007) Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses. Adv Virol 152(4):687–696. doi:10.1007/s00705-006-0903-z
Funk A, Truong K, Nagasaki T, Torres S, Floden N, Melian EB, Edmonds J, Dong HP, Shi PY, Khromykh AA (2010) RNA structures required for production of subgenomic flavivirus RNA. J Virol 84(21):11407–11417. doi:10.1128/jvi.01159-10
Sironi M, Forni D, Clerici M, Cagliani R (2016) Nonstructural proteins are preferential positive selection targets in Zika virus and related flaviviruses. Plos Negl Trop Dis. doi:10.1371/journal.pntd.0004978
Bollati M, Alvarez K, Assenberg R, Baronti C, Canard B, Cook S, Coutard B, Decroly E, de Lamballerie X, Gould EA, Grard G, Grimes JM, Hilgenfeld R, Jansson AM, Malet H, Mancini EJ, Mastrangelo E, Mattevi A, Milani M, Moureau G, Neyts J, Owens RJ, Ren JS, Selisko B, Speroni S, Steuber H, Stuart DI, Unge T, Bolognesi M (2010) Structure and functionality in flavivirus NS-proteins: perspectives for drug design. Antiviral Res 87(2):125–148. doi:10.1016/j.antiviral.2009.11.009
Egloff MP, Benarroch D, Selisko B, Romette JL, Canard B (2002) An RNA cap (nucleoside-2’-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization. EMBO J 21(11):2757–2768. doi:10.1093/emboj/21.11.2757
Dong H, Chang DC, Hua MH, Lim SP, Chionh YH, Hia F, Lee YH, Kukkaro P, Lok SM, Dedon PC, Shi PY (2012) 2’-O methylation of internal adenosine by flavivirus NS5 methyltransferase. PLoS Pathog 8(4):e1002642. doi:10.1371/journal.ppat.1002642
Langberg SR, Moss B (1981) Post-transcriptional modifications of mRNA. Purification and characterization of cap I and cap II RNA (nucleoside-2’-)-methyltransferases from HeLa cells. J Biol Chem 256(19):10054–10060
Dong HP, Zhang B, Shi PY (2008) Flavivirus methyltransferase: a novel antiviral target. Antiviral Res 80(1):1–10. doi:10.1016/j.antiviral.2008.05.003
Dong HP, Fink K, Zust R, Lim SP, Qin CF, Shi PY (2014) Flavivirus RNA methylation. J Gen Virol 95:763–778. doi:10.1099/vir.0.062208-0
Brecher M, Chen H, Liu B, Banavali NK, Jones SA, Zhang J, Li Z, Kramer LD, Li H (2015) Novel broad spectrum inhibitors targeting the flavivirus methyltransferase. PLoS One. doi:10.1371/journal.pone.0130062
Stephen P, Baz M, Boivin G, Lin SX (2016) Structural insight into NS5 of Zika virus leading to the discovery of MTase inhibitors. J Am Chem Soc 138(50):16212–16215. doi:10.1021/jacs.6b10399
Hamil RL, Hoehn MM (1973) A9145, a new adenine-containing antifungal antibiotic. I. Discovery and isolation. J Antibiot (Tokyo) 26(8):463–465
Zhang J, Zheng YG (2016) SAM/SAH analogs as versatile tools for SAM-dependent methyltransferases. ACS Chem Biol 11(3):583–597. doi:10.1021/acschembio.5b00812
Coloma J, Jain R, Rajashankar KR, Garcia-Sastre A, Aggarwal AK (2016) Structures of NS5 methyltransferase from Zika virus. Cell Rep 16(12):3097–3102. doi:10.1016/j.celrep.2016.08.091
Zhang C, Feng T, Cheng J, Li Y, Yin X, Zeng W, Jin X, Li Y, Guo F, Jin T (2016) Structure of the NS5 methyltransferase from Zika virus and implications in inhibitor design. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2016.11.098
Coutard B, Barral K, Lichiere J, Selisko B, Martin B, Aouadi W, Lombardia MO, Debart F, Vasseur JJ, Guillemot JC, Canard B, Decroly E (2017) Zika virus methyltransferase: structure and functions for drug design perspectives. J Virol. doi:10.1128/JVI.02202-16
Studier FW (2005) Protein production by auto-induction in high-density shaking cultures. Protein Expr Purif 41(1):207–234. doi:10.1016/j.pep.2005.01.016
Baumlova A, Chalupska D, Rozycki B, Jovic M, Wisniewski E, Klima M, Dubankova A, Kloer DP, Nencka R, Balla T, Boura E (2014) The crystal structure of the phosphatidylinositol 4-kinase IIalpha. EMBO Rep 15(10):1085–1092. doi:10.15252/embr.201438841
Mejdrova I, Chalupska D, Kogler M, Sala M, Plackova P, Baumlova A, Hrebabecky H, Prochazkova E, Dejmek M, Guillon R, Strunin D, Weber J, Lee G, Birkus G, Mertlikova-Kaiserova H, Boura E, Nencka R (2015) Highly selective phosphatidylinositol 4-kinase IIIbeta inhibitors and structural insight into their mode of action. J Med Chem 58(9):3767–3793. doi:10.1021/acs.jmedchem.5b00499
Rezabkova L, Boura E, Herman P, Vecer J, Bourova L, Sulc M, Svoboda P, Obsilova V, Obsil T (2010) 14-3-3 protein interacts with and affects the structure of RGS domain of regulator of G protein signaling 3 (RGS3). J Struct Biol 170(3):451–461. doi:10.1016/j.jsb.2010.03.009
Klima M, Toth DJ, Hexnerova R, Baumlova A, Chalupska D, Tykvart J, Rezabkova L, Sengupta N, Man P, Dubankova A, Humpolickova J, Nencka R, Veverka V, Balla T, Boura E (2016) Structural insights and in vitro reconstitution of membrane targeting and activation of human PI4KB by the ACBD3 protein. Sci Rep 6:23641. doi:10.1038/srep23641
McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ (2007) Phaser crystallographic software. J Appl Crystallogr 40(pt 4):658–674. doi:10.1107/S0021889807021206
Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, McCoy AJ, Moriarty NW, Oeffner R, Read RJ, Richardson DC, Richardson JS, Terwilliger TC, Zwart PH (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66(Pt 2):213–221. doi:10.1107/S0907444909052925
Jansson AM, Jakobsson E, Johansson P, Lantez V, Coutard B, de Lamballerie X, Unge T, Jones TA (2009) Structure of the methyltransferase domain from the Modoc virus, a flavivirus with no known vector. Acta Crystallogr D Biol Crystallogr 65(pt 8):796–803. doi:10.1107/S0907444909017260
Barton DHR, Gero SD, Quicletsire B, Samadi M (1991) Expedient synthesis of natural (S)-sinefungin and of its C-6’ epimer. J Chem Soc Perk T 1(5):981–985. doi:10.1039/p19910000981
Lim SP, Sonntag LS, Noble C, Nilar SH, Ng RH, Zou G, Monaghan P, Chung KY, Dong HP, Liu BP, Bodenreider C, Lee G, Ding M, Chan WL, Wang G, Jian YL, Chao AT, Lescar J, Yin Z, Vedananda TR, Keller TH, Shi PY (2011) Small molecule inhibitors that selectively block dengue virus methyltransferase. J Biol Chem 286(8):6233–6240. doi:10.1074/jbc.M110.179184
Franca GV, Schuler-Faccini L, Oliveira WK, Henriques CM, Carmo EH, Pedi VD, Nunes ML, Castro MC, Serruya S, Silveira MF, Barros FC, Victora CG (2016) Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet 388(10047):891–897. doi:10.1016/S0140-6736(16)30902-3
Acknowledgements
The Project was also supported by Project InterBioMed LO1302 from Ministry of Education of the Czech Republic, the support of the Academy of Sciences of the Czech Republic (RVO: 61388963) is also acknowledged.
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Hercik, K., Brynda, J., Nencka, R. et al. Structural basis of Zika virus methyltransferase inhibition by sinefungin. Arch Virol 162, 2091–2096 (2017). https://doi.org/10.1007/s00705-017-3345-x
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DOI: https://doi.org/10.1007/s00705-017-3345-x