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Antiviral evaluation of 1,4-disubstituted-1,2,3-triazole derivatives against Chikungunya virus

    Vitor Won-Held Rabelo

    Programa de Pós-graduação em Ciências e Biotecnologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, CEP, 24210-201, Brazil

    ,
    Verônica Diniz da Silva

    Laboratório de Síntese Orgânica, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, CEP, 22451-900, Brazil

    ,
    Maria Leonisa Sanchez Nuñez

    Programa de Pós-graduação em Ciências e Biotecnologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, CEP, 24210-201, Brazil

    ,
    Leonardo dos Santos Corrêa Amorim

    Programa de Pós-graduação em Ciências e Biotecnologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, CEP, 24210-201, Brazil

    Gerência de Desenvolvimento Tecnológico, Instituto Vital Brazil, Niterói, RJ, 24230-410, Brazil

    ,
    Camilla Djenne Buarque

    Laboratório de Síntese Orgânica, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, RJ, CEP, 22451-900, Brazil

    ,
    Richard J Kuhn

    Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA

    Purdue Institute of Inflammation, Immunology, & Infectious Disease, Purdue University, West Lafayette, IN 47907, USA

    ,
    Paula Alvarez Abreu

    Instituto de Biodiversidade e Sustentabilidade (NUPEM), Universidade Federal do Rio de Janeiro, Macaé, RJ, CEP, 27965-045, Brazil

    &
    Izabel Christina Nunes de Palmer Paixão

    *Author for correspondence:

    E-mail Address: izabelpaixao@id.uff.br

    Programa de Pós-graduação em Ciências e Biotecnologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, CEP, 24210-201, Brazil

    Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, CEP, 24210-201, Brazil

    Programas de Pós-graduação em Biotecnologia Marinha e de Neurologia, Universidade Federal Fluminense, Niterói, RJ, Brazil

    Published Online:https://doi.org/10.2217/fvl-2023-0142

    Aim: This work aimed to investigate the antiviral activity of two 1,4-disubstituted-1,2,3-triazole derivatives (1 and 2) against Chikungunya virus (CHIKV) replication. Materials & methods: Cytotoxicity was analyzed using colorimetric assays and the antiviral potential was evaluated using plaque assays and computational tools. Results: Compound 2 showed antiviral activity against CHIKV 181-25 in BHK-21 and Vero cells. Also, this compound presented a higher activity against CHIKV BRA/RJ/18 in Vero cells, like compound 1. Compound 2 exhibited virucidal activity and inhibited virus entry while compound 1 inhibited virus release. Molecular docking suggested that these derivatives inhibit nsP1 protein while compound 1 may also target capsid protein. Conclusion: Both compounds exhibit promising antiviral activity against CHIKV by blocking different steps of virus replication.

    Tweetable abstract

    Two 1,2,3-triazole derivatives against #Chikungunya virus showed promising antiviral activity, acting at different steps of the virus replication cycle.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Kril V, Aiqui-Reboul-Paviet O, Briant L, Amara A. New insights into chikungunya virus infection and pathogenesis. Annu. Rev. Virol. 8(1), 327–347 (2021).
    • 2. Weaver SC. Arrival of chikungunya virus in the new world: prospects for spread and impact on public health. PLOS Negl. Trop. Dis. 8(6), e2921 (2014).
    • 3. Puntasecca CJ, King CH, Labeaud AD. Measuring the global burden of chikungunya and Zika viruses: a systematic review. PLOS Negl. Trop. Dis. 15(3), e0009055 (2021).
    • 4. Sharif N, Sarkar MK, Ferdous RN et al. Molecular epidemiology, evolution and reemergence of chikungunya virus in South Asia. Front. Microbiol. 12, (2021).
    • 5. Manzoor KN, Javed F, Ejaz M et al. The global emergence of chikungunya infection: an integrated view. Rev. Med. Virol. 32(3), e2287 (2022).
    • 6. Wimalasiri-Yapa BMCR, Stassen L, Huang X et al. Chikungunya virus in Asia - Pacific: a systematic review. Emerg. Microbes Infect. 8(1), 70–79 (2019).
    • 7. de Lima Cavalcanti TYV, Pereira MR, Paula SO, Franca RFO. A review on chikungunya virus epidemiology, pathogenesis and current vaccine development. Viruses 14(5), 969 (2022).
    • 8. Chala B, Hamde F. Emerging and re-emerging vector-borne infectious diseases and the challenges for control: a review. Front. Public Heal. 9, (2021).
    • 9. ECDC. Chikungunya worldwide overview (2023). www.ecdc.europa.eu/en/chikungunya-monthly
    • 10. Paixão ES, Rodrigues LC, Costa MDCN et al. Chikungunya chronic disease: a systematic review and meta-analysis. Trans. R. Soc. Trop. Med. Hyg. 112(7), 301–316 (2018).
    • 11. Ganesan V, Duan B, Reid S. Chikungunya virus: pathophysiology, mechanism, and modeling. Viruses 9(12), 1–14 (2017).
    • 12. van Ewijk R, Huibers MHW, Manshande ME et al. Neurologic sequelae of severe chikungunya infection in the first 6 months of life: a prospective cohort study 24-months post-infection. BMC Infect. Dis. 21(1), 179 (2021).
    • 13. Gao S, Song S, Zhang L. Recent progress in vaccine development against chikungunya virus. Front. Microbiol. 10, 1–10 (2019).
    • 14. Schneider M, Narciso-Abraham M, Hadl S et al. Safety and immunogenicity of a single-shot live-attenuated chikungunya vaccine: a double-blind, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 401(10394), 2138–2147 (2023).
    • 15. Battisti V, Urban E, Langer T. Antivirals against the Chikungunya Virus. Viruses 13(7), 1307 (2021). •• This study reinforce that the search for novel specific antivirals against CHIKV is highly needed.
    • 16. Bozorov K, Zhao J, Aisa HA. 1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: a recent overview. Bioorg. Med. Chem. 27(16), 3511–3531 (2019).
    • 17. Bonandi E, Christodoulou MS, Fumagalli G, Perdicchia D, Rastelli G, Passarella D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov. Today 22(10), 1572–1581 (2017).
    • 18. Kharb R, Yar MS, Sharma PC. Recent advances and future perspectives of triazole analogs as promising antiviral agents. Mini-Reviews Med. Chem. 11(1), 84–96 (2011).
    • 19. da S M Forezi L, Lima CGS, Amaral AAP et al. Bioactive 1,2,3-triazoles: an account on their synthesis, structural diversity and biological applications. Chem. Rec. 21(10), 2782–2807 (2021).
    • 20. da Silva VD, de Faria BM, Colombo E et al. Design, synthesis, structural characterization and in vitro evaluation of new 1,4-disubstituted-1,2,3-triazole derivatives against glioblastoma cells. Bioorg. Chem. 83, 87–97 (2019). •• This is the first report of the studied triazole derivatives.
    • 21. Almeida-Souza F, da Silva VD, Silva GX et al. 1,4-disubstituted-1,2,3-triazole compounds induce ultrastructural alterations in Leishmania amazonensis promastigote: an in vitro antileishmanial and in silico pharmacokinetic study. Int. J. Mol. Sci. 21(18), 1–20 (2020).
    • 22. Viegas DJ, da Silva VD, Buarque CD, Bloom DC, Abreu PA. Antiviral activity of 1,4-disubstituted-1,2,3-triazoles against HSV-1 in vitro. Antivir. Ther. 25(8), 399–410 (2020). •• Our group uncovered the antiviral activity of the studied compounds against Herpes simplex virus type 1.
    • 23. Cirne-Santos CC, Barros CS, Nogueira CCR et al. Inhibition by marine algae of chikungunya virus isolated from patients in a recent disease outbreak in rio de janeiro. Front. Microbiol. 10, 1–11 (2019).
    • 24. Khan M, Santhosh SR, Tiwari M, Lakshmana Rao PV, Parida M. Assessment of in vitro prophylactic and therapeutic efficacy of chloroquine against chikungunya virus in vero cells. J. Med. Virol. 82(5), 817–824 (2010).
    • 25. Fox JM, Long F, Edeling MA et al. Broadly neutralizing alphavirus antibodies bind an epitope on E2 and inhibit entry and egress. Cell 163(5), 1095–1107 (2015).
    • 26. Lani R, Hassandarvish P, Shu MH et al. Antiviral activity of selected flavonoids against Chikungunya virus. Antiviral Res. 133, 50–61 (2016).
    • 27. O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: an open chemical toolbox. J. Cheminform. 3(1), 33 (2011).
    • 28. Rabelo VWH, de Palmer Paixão ICN, Abreu PA. Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches. J. Mol. Model. 28(10), 311 (2022). • Computational tools can support the development of novel anti-CHIKV compounds and aid the investigation of their mechanism of action.
    • 29. Jones R, Bragagnolo G, Arranz R, Reguera J. Capping pores of alphavirus nsP1 gate membranous viral replication factories. Nature 589(7843), 615–619 (2021).
    • 30. Zhang K, Law YS, Law MCY, Tan YB, Wirawan M, Luo D. Structural insights into viral RNA capping and plasma membrane targeting by Chikungunya virus nonstructural protein 1. Cell Host Microbe 29(5), 757–764.e3 (2021).
    • 31. Fatma B, Kumar R, Singh VA et al. Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection. Antiviral Res. 179, DOI: 10.1016/j.antiviral.2020.104808 (2020).
    • 32. Delang L, Li C, Tas A et al. The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection. Sci. Rep. 6(1), 1–10 (2016).
    • 33. Ivanova L, Rausalu K, Žusinaite E, Tammiku-Taul J, Merits A, Karelson M. 1,3-thiazolbenzamide derivatives as chikungunya virus nsP2 protease inhibitors. ACS Omega 6(8), 5786–5794 (2021).
    • 34. Ferraz AC, Moraes TFS, Nizer WSDC et al. Virucidal activity of proanthocyanidin against Mayaro virus. Antiviral Res. 168, 76–81 (2019).
    • 35. Roques P, Thiberville SD, Dupuis-Maguiraga L et al. Paradoxical effect of chloroquine treatment in enhancing chikungunya virus infection. Viruses. 10(5), 268 (2018). • This study reported that chloroquine fails to combat CHIKV infection in humans and non-human primates.
    • 36. De Lamballerie X, Boisson V, Reynier JC et al. On chikungunya acute infection and chloroquine treatment. Vector-Borne Zoonotic Dis. 8(6), 837–839 (2008).
    • 37. Cirne-Santos CC, de Souza Barros C, de Oliveira MC et al. In vitro studies on the inhibition of replication of Zika and chikungunya viruses by dolastane isolated from seaweed Canistrocarpus cervicornis. Sci. Rep. 10(1), 1–10 (2020).
    • 38. Franco EJ, Rodriquez JL, Pomeroy JJ, Hanrahan KC, Brown AN. The effectiveness of antiviral agents with broad-spectrum activity against chikungunya virus varies between host cell lines. Antivir. Chem. Chemother. 26, (2018).
    • 39. Rothan HA, Bahrani H, Mohamed Z et al. A combination of doxycycline and ribavirin alleviated chikungunya infection. PLOS ONE 10(5), 1–15 (2015).
    • 40. Ravichandran R, Manian M. Ribavirin therapy for chikungunya arthritis. J. Infect. Dev. Ctries. 2(2), 140–142 (2008).
    • 41. Sinclair SM, Jones JK, Miller RK, Greene MF, Kwo PY, Maddrey WC. The ribavirin pregnancy registry: an interim analysis of potential teratogenicity at the mid-point of enrollment. Drug Saf. 40(12), 1205–1218 (2017). • This study report that the clinical use of ribavirin has some limitations, which supports the search for novel alternatives to treat CHIKV infections.
    • 42. Gigante A, Canela MD, Delang L et al. Identification of [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones as novel inhibitors of chikungunya virus replication. J. Med. Chem. 57(10), 4000–4008 (2014).
    • 43. Gigante A, Gómez-SanJuan A, Delang L et al. Antiviral activity of [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones against chikungunya virus targeting the viral capping nsP1. Antiviral Res. 144, 216–222 (2017).
    • 44. Gómez-Sanjuan A, Gamo AM, Delang L et al. Inhibition of the replication of different strains of chikungunya virus by 3-Aryl-[1,2,3]triazolo[4,5-d] pyrimidin-7(6 H)-ones. ACS Infect. Dis. 4(4), 605–619 (2018). • This study reports a triazole derivative with antiviral potential against the replication of different CHIKV strains in Vero cells.
    • 45. Cassell S, Edwards J, Brown DT. Effects of lysosomotropic weak bases on infection of BHK-21 cells by Sindbis virus. J. Virol. 52(3), 857–864 (1984).
    • 46. Delogu I, Pastorino B, Baronti C, Nougairède A, Bonnet E, de Lamballerie X. In vitro antiviral activity of arbidol against Chikungunya virus and characteristics of a selected resistant mutant. Antiviral Res. 90(3), 99–107 (2011).
    • 47. Oo A, Rausalu K, Merits A et al. Deciphering the potential of baicalin as an antiviral agent for Chikungunya virus infection. Antiviral Res. 150, 101–111 (2018).
    • 48. Ho YJ, Wang YM, Lu JW et al. Suramin inhibits chikungunya virus entry and transmission. PLOS ONE 10(7), 1–18 (2015).
    • 49. Delang L, Guerrero NS, Tas A et al. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. J. Antimicrob. Chemother. 69(10), 2770–2784 (2014).
    • 50. Li N, Wang Z, Wang R et al. In vitro inhibition of alphaviruses by lycorine. Virol. Sin. 36(6), 1465–1474 (2021).
    • 51. Wan JJ, Brown RS, Kielian M. Berberine chloride is an alphavirus inhibitor that targets nucleocapsid assembly. MBio 11(3), 1–21 (2020).
    • 52. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int. J. Antimicrob. Agents 55(5), DOI: 10.1016/j.ijantimicag.2020.105938 (2020).
    • 53. Galati S, Di Stefano M, Martinelli E, Poli G, Tuccinardi T. Recent advances in in silico target fishing. Molecules 26(17), 5124 (2021).
    • 54. Abdelnabi R, Kovacikova K, Moesslacher J et al. Novel class of chikungunya virus small molecule inhibitors that targets the viral capping machinery. Antimicrob. Agents Chemother. 64(7), e00649–20 (2020).
    • 55. Mudgal R, Mahajan S, Tomar S. Inhibition of Chikungunya virus by an adenosine analog targeting the SAM-dependent nsP1 methyltransferase. FEBS Lett. 594(4), 678–694 (2020).
    • 56. Mudgal R, Bharadwaj C, Dubey A et al. Selective estrogen receptor modulators limit alphavirus infection by targeting the viral capping enzyme nsP1. Antimicrob. Agents Chemother. 66(3), e0194321 (2022).
    • 57. Adalja A, Inglesby T. Broad-spectrum antiviral agents: a crucial pandemic tool. Expert Rev. Anti. Infect. Ther. 17(7), 467–470 (2019).
    • 58. Pérez-Pérez MJ, Delang L, Ng LFP, Priego EM. Chikungunya virus drug discovery: still a long way to go? Expert Opin. Drug Discov. 14(9), 855–866 (2019).