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image of Druggable Targets in Zika Virus: A Systematic Review of Therapeutic Opportunities in Brazil

Abstract

Introduction

Zika virus (ZIKV), a flavivirus primarily transmitted by Aedes aegypti, became a major global health concern during the 2015–2016 outbreak, particularly in Brazil. Its association with congenital malformations and neurological disorders underscores the urgent need for effective therapeutic interventions. This review explores molecular targets for ZIKV treatment within the Brazilian context.

Method

A systematic search was conducted using PubMed, ScienceDirect, and Scopus for studies published between 2004 and 2024. Inclusion criteria focused on studies identifying druggable molecular targets related to viral replication, immune evasion, or host-virus interactions. Key search terms included “Zika virus,” “molecular targets,” “Brazil,” “antiviral,” and “drug discovery.”

Results

The review identified several critical viral proteins, NS1, NS3, NS5, and the envelope protein, as potential drug targets. Host cellular factors essential for viral survival were also highlighted. Technologies such as high-throughput screening, molecular docking, and structural genomics contributed significantly to the identification and validation of these targets.

Discussion

Although promising targets have been identified, therapeutic development is hindered by the genetic variability of ZIKV and its antigenic similarity to other flaviviruses, notably the dengue virus. These challenges complicate the specificity and efficacy of drugs. Nevertheless, Brazil has made strides in research infrastructure and collaborations to tackle these obstacles.

Conclusion

This review synthesizes current knowledge on ZIKV molecular targets and ongoing drug discovery efforts. The findings support the strategic development of antivirals and emphasize the necessity for sustained investment in research to mitigate future ZIKV outbreaks in Brazil and globally.

© 2025 Bentham Science Publishers
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2025-08-21
2025-11-09

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References

  1. Lazear H.M. Diamond M.S. Zika Virus: New clinical syndromes and its emergence in the western hemisphere. J. Virol. 2016 90 10 4864 4875 10.1128/JVI.00252‑16 26962217
    [Google Scholar]
  2. Monteiro F.J.C. Mourão F.R.P. Ribeiro E.S.D.A. Rêgo M.O.S. Frances P.A.C. Souto R.N.P. Façanha M.S. Tahmasebi R. Costa A.C. Prevalence of dengue, Zika and chikungunya viruses in Aedes (Stegomyia) aegypti (Diptera: Culicidae) in a medium-sized city, Amazon, Brazil. Rev. Inst. Med. Trop. São Paulo 2020 62 e10 10.1590/s1678‑9946202062010 32049261
    [Google Scholar]
  3. Lowe R. Barcellos C. Brasil P. Cruz O. Honório N. Kuper H. Carvalho M. The zika virus epidemic in brazil: from discovery to future implications. Int. J. Environ. Res. Public Health 2018 15 1 96 10.3390/ijerph15010096 29315224
    [Google Scholar]
  4. Garcia Serpa Osorio-de-Castro C. Silva Miranda E. Machado de Freitas C. Rochel de Camargo K. Cranmer H.H. The zika virus outbreak in brazil: knowledge gaps and challenges for risk reduction. Am. J. Public Health 2017 107 6 960 965 10.2105/AJPH.2017.303705 28426311
    [Google Scholar]
  5. Quanquin N. Wang L. Cheng G. Potential for treatment and a Zika virus vaccine. Curr. Opin. Pediatr. 2017 29 1 114 121 10.1097/MOP.0000000000000441 27906864
    [Google Scholar]
  6. Mottin M. Borba J.V.V.B. Braga R.C. Torres P.H.M. Martini M.C. Proenca-Modena J.L. Judice C.C. Costa F.T.M. Ekins S. Perryman A.L. Horta Andrade C. The A–Z of Zika drug discovery. Drug Discov. Today 2018 23 11 1833 1847 10.1016/j.drudis.2018.06.014 29935345
    [Google Scholar]
  7. Boldescu V. Behnam M.A.M. Vasilakis N. Klein C.D. Broad-spectrum agents for flaviviral infections: Dengue, Zika and beyond. Nat. Rev. Drug Discov. 2017 16 8 565 586 10.1038/nrd.2017.33 28473729 PMCID: PMC5925760
    [Google Scholar]
  8. Postler T.S. Beer M. Blitvich B.J. Bukh J. de Lamballerie X. Drexler J.F. Imrie A. Kapoor A. Karganova G.G. Lemey P. Lohmann V. Simmonds P. Smith D.B. Stapleton J.T. Kuhn J.H. Renaming of the genus Flavivirus to Orthoflavivirus and extension of binomial species names within the family Flaviviridae. Arch. Virol. 2023 168 9 224 10.1007/s00705‑023‑05835‑1 37561168
    [Google Scholar]
  9. Zhao R. Wang M. Cao J. Shen J. Zhou X. Wang D. Cao J. Flavivirus: From structure to therapeutics development. Life 2021 11 7 615 10.3390/life11070615 34202239
    [Google Scholar]
  10. Mottin M. Borba J.V.V.B. Melo-Filho C.C. Neves B.J. Muratov E. Torres P.H.M. Braga R.C. Perryman A. Ekins S. Andrade C.H. Computational drug discovery for the Zika virus. Braz J. Pharm. Sci. 2018 54 spe e01002 10.1590/s2175‑97902018000001002
    [Google Scholar]
  11. Page M.J. McKenzie J.E. Bossuyt P.M. Boutron I. Hoffmann T.C. Mulrow C.D. Shamseer L. Tetzlaff J.M. Akl E.A. Brennan S.E. Chou R. Glanville J. Grimshaw J.M. Hróbjartsson A. Lalu M.M. Li T. Loder E.W. Mayo-Wilson E. McDonald S. McGuinness L.A. Stewart L.A. Thomas J. Tricco A.C. Welch V.A. Whiting P. Moher D. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021 372 71 n71 10.1136/bmj.n71 33782057
    [Google Scholar]
  12. Bressanelli S. Stiasny K. Allison S.L. Stura E.A. Duquerroy S. Lescar J. Heinz F.X. Rey F.A. Structure of a flavivirus envelope glycoprotein in its low-pH-induced membrane fusion conformation. EMBO J. 2004 23 4 728 738 10.1038/sj.emboj.7600064 14963486
    [Google Scholar]
  13. Feng Y. Recent advances in the study of zika virus structure, drug targets, and inhibitors. Front. Pharmacol. 2024 15 1418516 10.3389/fphar.2024.1418516 39011504
    [Google Scholar]
  14. Yuan S. Chan J.F.W. den-Haan H. Chik K.K.H. Zhang A.J. Chan C.C.S. Poon V.K.M. Yip C.C.Y. Mak W.W.N. Zhu Z. Zou Z. Tee K.M. Cai J.P. Chan K.H. de la Peña J. Pérez-Sánchez H. Cerón-Carrasco J.P. Yuen K.Y. Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo. Antiviral Res. 2017 145 33 43 10.1016/j.antiviral.2017.07.007 28712942
    [Google Scholar]
  15. Elfiky A.A. Ibrahim I.M. Zika virus envelope – heat shock protein A5 (GRP78) binding site prediction. J. Biomol. Struct. Dyn. 2021 39 14 5248 5260 10.1080/07391102.2020.1784794 32579073
    [Google Scholar]
  16. Graham S.D. Tu H.A. McElvany B.D. Graham N.R. Grinyo A. Davidson E. Doranz B.J. Diehl S.A. de Silva A.M. Markmann A.J. A novel antigenic site spanning domains i and iii of the zika virus envelope glycoprotein is the target of strongly neutralizing human monoclonal antibodies. J. Virol. 2021 95 9 e02423 e20 10.1128/JVI.02423‑20 33597214
    [Google Scholar]
  17. Faye O. Faye O. Dupressoir A. Weidmann M. Ndiaye M. Alpha Sall, A One-step RT-PCR for detection of Zika virus. J. Clin. Virol. 2008 43 1 96 101 10.1016/j.jcv.2008.05.005 18674965
    [Google Scholar]
  18. Bernatchez J.A. Tran L.T. Li J. Luan Y. Siqueira-Neto J.L. Li R. Drugs for the treatment of zika virus infection. J. Med. Chem. 2020 63 2 470 489 10.1021/acs.jmedchem.9b00775 31549836
    [Google Scholar]
  19. Duan W. Song H. Wang H. Chai Y. Su C. Qi J. Shi Y. Gao G.F. The crystal structure of Zika virus NS 5 reveals conserved drug targets. EMBO J. 2017 36 7 919 933 10.15252/embj.201696241 28254839
    [Google Scholar]
  20. Wang L. Liang R. Gao Y. Li Y. Deng X. Xiang R. Zhang Y. Ying T. Jiang S. Yu F. Development of small-molecule inhibitors against zika virus infection. Front. Microbiol. 2019 10 2725 10.3389/fmicb.2019.02725 31866959
    [Google Scholar]
  21. Jain R. Butler K.V. Coloma J. Jin J. Aggarwal A.K. Development of a S-adenosylmethionine analog that intrudes the RNA-cap binding site of Zika methyltransferase. Sci. Rep. 2017 7 1 1632 10.1038/s41598‑017‑01756‑7 28487506
    [Google Scholar]
  22. Wu H. Huang X.Y. Sun M.X. Wang Y. Zhou H.Y. Tian Y. He B. Li K. Li D.Y. Wu A.P. Wang H. Qin C.F. Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids. Nat. Commun. 2023 14 1 5541 10.1038/s41467‑023‑41158‑0 37684223
    [Google Scholar]
  23. Ren W. Fu C. Zhang Y. Ju X. Jiang X. Song J. Gong M. Li Z. Fan W. Yao J. Ding Q. Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2. Proc. Natl. Acad. Sci. USA 2024 121 34 e2403235121 10.1073/pnas.2403235121 39145933
    [Google Scholar]
  24. Song H. Qi J. Haywood J. Shi Y. Gao G.F. Zika virus NS1 structure reveals diversity of electrostatic surfaces among flaviviruses. Nat. Struct. Mol. Biol. 2016 23 5 456 458 10.1038/nsmb.3213 27088990
    [Google Scholar]
  25. Abrams R.P.M. Solis J. Nath A. Therapeutic approaches for zika virus infection of the nervous system. Neurotherapeutics 2017 14 4 1027 1048 10.1007/s13311‑017‑0575‑2 28952036
    [Google Scholar]
  26. Kobres P.Y. Chretien J.P. Johansson M.A. Morgan J.J. Whung P.Y. Mukundan H. Del Valle S.Y. Forshey B.M. Quandelacy T.M. Biggerstaff M. Viboud C. Pollett S. A systematic review and evaluation of Zika virus forecasting and prediction research during a public health emergency of international concern. PLoS Negl. Trop. Dis. 2019 13 10 e0007451 10.1371/journal.pntd.0007451 31584946
    [Google Scholar]
  27. Agrelli A. de Moura R.R. Crovella S. Brandão L.A.C. ZIKA virus entry mechanisms in human cells. Infect. Genet. Evol. 2019 69 22 29 10.1016/j.meegid.2019.01.018 30658214
    [Google Scholar]
  28. Lundberg R. Melén K. Westenius V. Jiang M. Österlund P. Khan H. Vapalahti O. Julkunen I. Kakkola L. Zika virus non-structural protein ns5 inhibits the rig-i pathway and interferon lambda 1 promoter activation by targeting ikk epsilon. Viruses 2019 11 11 1024 10.3390/v11111024 31690057
    [Google Scholar]
  29. Valente A.P. Moraes A.H. Zika virus proteins at an atomic scale: How does structural biology help us to understand and develop vaccines and drugs against Zika virus infection? J. Venom. Anim. Toxins Incl. Trop. Dis. 2019 25 e20190013 10.1590/1678‑9199‑jvatitd‑2019‑0013 31523227
    [Google Scholar]
  30. Telehany S.M. Humby M.S. McGee T.D. Riley S.P. Jacobs A. Rizzo R.C. Identification of Zika virus inhibitors using homology modeling and similarity-based screening to target glycoprotein E. Biochemistry 2020 59 39 3709 3724 10.1021/acs.biochem.0c00458 32876433
    [Google Scholar]
  31. Zeng J. Dong S. Luo Z. Xie X. Fu B. Li P. Liu C. Yang X. Chen Y. Wang X. Liu Z. Wu J. Yan Y. Wang F. Chen J.F. Zhang J. Long G. Goldman S.A. Li S. Zhao Z. Liang Q. The Zika virus capsid disrupts corticogenesis by suppressing dicer activity and mirna biogenesis. Cell Stem Cell 2020 27 4 618 632.e9 10.1016/j.stem.2020.07.012 32763144
    [Google Scholar]
  32. Wang B. Thurmond S. Zhou K. Sánchez-Aparicio M.T. Fang J. Lu J. Gao L. Ren W. Cui Y. Veit E.C. Hong H. Evans M.J. O’Leary S.E. García-Sastre A. Zhou Z.H. Hai R. Song J. Structural basis for STAT2 suppression by flavivirus NS5. Nat. Struct. Mol. Biol. 2020 27 10 875 885 10.1038/s41594‑020‑0472‑y 32778820
    [Google Scholar]
  33. Esswein S.R. Gristick H.B. Jurado A. Peace A. Keeffe J.R. Lee Y.E. Voll A.V. Saeed M. Nussenzweig M.C. Rice C.M. Robbiani D.F. MacDonald M.R. Bjorkman P.J. Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody. Proc. Natl. Acad. Sci. USA 2020 117 18 9865 9875 10.1073/pnas.1919269117 32321830
    [Google Scholar]
  34. Duarte G. Miranda A.E. Bermúdez X.P.D. Saraceni V. Martínez-Espinosa F.E. rotocolo brasileiro para infecções sexualmente transmissíveis 2020: Infecção pelo vírus Zika. Epidemiol. Serv Saude 2021 30 spe1 e2020609 10.1590/s1679‑4974202100017.esp1 33729407
    [Google Scholar]
  35. Song W. Zhang H. Zhang Y. Chen Y. Lin Y. Han Y. Jiang J. Identification and characterization of zika virus ns5 methyltransferase inhibitors. Front. Cell. Infect. Microbiol. 2021 11 665379 10.3389/fcimb.2021.665379 33898335
    [Google Scholar]
  36. Zhang C. Sultan S.A. T, R.; Chen, X. Biotechnological applications of S-adenosyl-methionine-dependent methyltransferases for natural products biosynthesis and diversification. Bioresour. Bioprocess. 2021 8 1 72 10.1186/s40643‑021‑00425‑y 38650197
    [Google Scholar]
  37. Bhatnagar P. Sreekanth G.P. Murali-Krishna K. Chandele A. Sitaraman R. Dengue virus non-structural protein 5 as a versatile, multi-functional effector in host–pathogen interactions. Front. Cell. Infect. Microbiol. 2021 11 574067 10.3389/fcimb.2021.574067 33816326
    [Google Scholar]
  38. Gupta A. Jain P. Venkatesh V. Agarwal A. Reddy D.H. Jain A. Prevalence of dengue, chikungunya, and zika viruses in febrile pregnant women: an observational study at a tertiary care hospital in North India. Am. J. Trop. Med. Hyg. 2022 106 1 168 173 10.4269/ajtmh.21‑0584 34607306
    [Google Scholar]
  39. Balint E. Montemarano A. Feng E. Ashkar A.A. From mosquito bites to sexual transmission: evaluating mouse models of zika virus infection. Viruses 2021 13 11 2244 10.3390/v13112244 34835050
    [Google Scholar]
  40. Li Q. Kang C. Structure and dynamics of zika virus protease and its insights into inhibitor design. Biomedicines 2021 9 8 1044 10.3390/biomedicines9081044 34440248 PMCID: PMC8394600
    [Google Scholar]
  41. Nascimento I.J.S. Santos-Júnior P.F.S. Aquino T.M. Araújo-Júnior J.X. Silva-Júnior E.F. Insights on Dengue and Zika NS5 RNA-dependent RNA polymerase (RdRp) inhibitors. Eur. J. Med. Chem. 2021 224 113698 10.1016/j.ejmech.2021.113698 34274831
    [Google Scholar]
  42. Roy A. Liu Q. Yang Y. Debnath A.K. Du L. Envelope protein-targeting zika virus entry inhibitors. Int. J. Mol. Sci. 2024 25 17 9424 10.3390/ijms25179424 39273370
    [Google Scholar]
  43. Kumar A. Kumar D. Jose J. Giri R. Mysorekar I.U. Drugs to limit Zika virus infection and implication for maternal-fetal health. Front Virol. 2022 2 928599 10.3389/fviro.2022.928599 37064602
    [Google Scholar]
  44. Mirza M.U. Alanko I. Vanmeert M. Muzzarelli K.M. Salo-Ahen O.M.H. Abdullah I. Kovari I.A. Claes S. De Jonghe S. Schols D. Schinazi R.F. Kovari L.C. Trant J.F. Ahmad S. Froeyen M. The discovery of Zika virus NS2B-NS3 inhibitors with antiviral activity via an integrated virtual screening approach. Eur. J. Pharm. Sci. 2022 175 106220 10.1016/j.ejps.2022.106220 35618201
    [Google Scholar]
  45. Zhang H. Xiao W. Zhao M. Zhao Y. Zhang Y. Lu D. Lu S. Zhang Q. Peng W. Shu L. Zhang J. Liu S. Zong K. Wang P. Ye B. Li S. Tan S. Zhang F. Zhou J. Liu P. Wu G. Lu X. Gao G.F. Liu W.J. The CD8+ and CD4+ T cell immunogen atlas of zika virus reveals e, ns1 and ns4 proteins as the vaccine targets. Viruses 2022 14 11 2332 10.3390/v14112332 36366430
    [Google Scholar]
  46. Xie X. Yu T. Li X. Zhang N. Foster L.J. Peng C. Huang W. He G. Recent advances in targeting the “undruggable” proteins: From drug discovery to clinical trials. Signal Transduct. Target. Ther. 2023 8 1 335 10.1038/s41392‑023‑01589‑z 37669923
    [Google Scholar]
  47. van den Elsen K. Chew B.L.A. Ho J.S. Luo D. Flavivirus nonstructural proteins and replication complexes as antiviral drug targets. Curr. Opin. Virol. 2023 59 101305 10.1016/j.coviro.2023.101305 36870091
    [Google Scholar]
  48. Zhou G.F. Li F. Xue J.X. Qian W. Gu X.R. Zheng C.B. Li C. Yang L.M. Xiong S.D. Zhou G.C. Zheng Y.T. Antiviral effects of the fused tricyclic derivatives of indoline and imidazolidinone on ZIKV infection and RdRp activities of ZIKV and DENV. Virus Res. 2023 326 199062 10.1016/j.virusres.2023.199062 36746341
    [Google Scholar]
  49. Membrane retention of west nile virus ns5 depends on ns1 or ns3 for enzymatic activity. Viruses 2024 16 8 1303 10.3390/v16081303 39205277 PMCID: PMC11360346
    [Google Scholar]
  50. Mazeaud C. Pfister S. Owen J.E. Pereira H.S. Charbonneau F. Robinson Z.E. Anton A. Bemis C.L. Sow A.A. Patel T.R. Neufeldt C.J. Scaturro P. Chatel-Chaix L. Zika virus remodels and hijacks IGF2BP2 ribonucleoprotein complex to promote viral replication organelle biogenesis. eLife 2024 13 RP94347 10.7554/eLife.94347.3 39565347
    [Google Scholar]
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Druggable Targets in Zika Virus: A Systematic Review of Therapeutic Opportunities in Brazil
Bentham Science Publishers ; https://doi.org/10.2174/0115680266388856250811094000
/content/journals/ctmc/10.2174/0115680266388856250811094000
/content/journals/ctmc/10.2174/0115680266388856250811094000
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  • Article Type:     Review Article
Keywords: Brazil ; ZIKA virus ; epidemic ; druggable targets

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