Serving the Society Since 1986
Advanced Search
Volume 41 Issue 4
August 2026
    Citation: Chunjiao Liu, Shixiang Pan, Mingxue Gao, Yumin Zhang, Leike Zhang, Bin Lin, Xiangrui Jiang. Recent progress in anti-Chikungunya virus drug discovery: Focus on the viral life cycle and direct-acting antivirals .VIROLOGICA SINICA, 2026, 41(4) : 735-752.  http://dx.doi.org/10.1016/j.virs.2026.07.001
    shu

    Recent progress in anti-Chikungunya virus drug discovery: Focus on the viral life cycle and direct-acting antivirals

    • a. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;

    • b. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China;

    • c. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;

    • d. School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei 230012, China;

    • e. Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;

    • f. University of Chinese Academy of Sciences, Beijing 100049, China

    • Chikungunya virus (CHIKV) belongs to the genus Alphavirus of the family Togaviridae. CHIKV infection generally causes severe clinical symptoms, including debilitating arthralgia, fever, hemorrhage and cutaneous rashes. In recent years, the transmission range of CHIKV has continued to expand, resulting in recurrent local outbreaks in densely populated and economically developed regions and posing a severe threat to public health. Accordingly, safe and effective anti-CHIKV therapeutics are urgently needed for the clinical treatment of infected patients. Nevertheless, no specific anti-CHIKV drugs have been approved for clinical use or advanced into clinical trials, and relevant research and development remain confined to the preclinical stage. This review systematically illustrates the key steps of the CHIKV life cycle, core viral components and vital functional domains, and summarizes the current research progress of anti-CHIKV agents. It comprehensively outlines the discovery strategies, structural optimization directions and activity evaluation approaches of anti-CHIKV small-molecule compounds, and further investigates their action targets. Notably, nsP2 and nsP4 represent promising targets for broad-spectrum anti-CHIKV even anti-alphavirus drug development due to their structural conservation across alphavirus species and druggable features. This work provides a solid theoretical basis and valuable reference for the future research and development of novel anti-CHIKV drugs.
    • 加载中

      1. Abdelnabi, R., Kovacikova, K., Moesslacher, J., Donckers, K., Battisti, V., Leyssen, P., Langer, T., Puerstinger, G., Querat, G., Li, C., Decroly, E., Tas, A., Marchand, A., Chaltin, P., Coutard, B., van Hemert, M., Neyts, J., Delang, L. 2020. Novel class of Chikungunya Virus small molecule inhibitors that targets the viral capping machinery. Antimicrob. Agents Chemother. 64, e00649-20.

      2. Agrawal, T., Siddqui, G., Dahiya, R., Patidar, A., Madan, U., Das, S., Asthana, S., Samal, S., Awasthi, A. 2024. Inhibition of early RNA replication in Chikungunya and Dengue virus by lycorine: in vitro and in silico studies. Biochem. Biophys. Res. Commun. 730, 150393.

      3. Ahmed, S.K., Haese, N.N., Cowan, J.T., Pathak, V., Moukha-Chafiq, O., Smith, V.J., Rodzinak, K.J., Ahmad, F., Zhang, S., Bonin, K.M., Streblow, A.D., Streblow, C.E., Kreklywich, C.N., Morrison, C., Sarkar, S., Moorman, N., Sander, W., Allen, R., DeFilippis, V., Tekwani, B.L., Wu, M., Hirsch, A.J., Smith, J.L., Tower, N.A., Rasmussen, L., Bostwick, R., Maddry, J.A., Ananthan, S., Gerdes, J.M., Augelli-Szafran, C.E., Suto, M.J., Morrison, T.E., Heise, M.T., Streblow, D.N., Pathak, A.K. 2021. Targeting Chikungunya virus replication by benzoannulene inhibitors. J. Med. Chem. 64, 4762-4786.

      4. Alagarasu, K., Kharikar, D., Roy, D., Patil, P., Cherian, S., Podila, N., Selvaraj, J., Parashar, D. 2025. Anti-Chikungunya activity of a cinnamic acid derivative: an in vitro and in silico study. Mol. Biotechnol. 68, 2000-2010.

      5. Antoine, A.-F., Montpellier, C., Cailliau, K., Browaeys-Poly, E., Vilain, J.-P., Dubuisson, J. 2007. The alphavirus 6K protein activates endogenous ionic conductances when expressed in xenopus oocytes. J. Membr. Biol., 215, 37-48.

      6. Arankalle, V.A., Shrivastava, S., Cherian, S., Gunjikar, R.S., Walimbe, A.M., Jadhav, S.M., Sudeep, A.B., Mishra, A.C. 2007. Genetic divergence of Chikungunya viruses in India (1963-2006) with special reference to the 2005-2006 explosive epidemic. J. Gen. Virol. 88, 1967-1976.

      7. Aschenbrenner, J.C., Godoy, A.S.d., Fairhead, M., Tomlinson, C.W.E., Winokan, M., Balcomb, B.H., Capkin, E., Chandran, A.V., Golding, M., Koekemoer, L., Lithgo, R.M., Marples, P.G., Ni, X., Thompson, W., Wild, C., Xavier, M.A.E., Fearon, D., Delft, F.v. 2024. Identifying novel chemical matter against the Chikungunya virus nsP3 macrodomain through crystallographic fragment screening. bioRxiv, doi:10.1101/2024.08.23.609196.

      8. Ballista, J.M.R., Hoover, A.J., Noble, J.T., Acciani, M.D., Miazgowicz, K.L., Harrison, S.A., Tabscott, G.A.L., Duncan, A., Barnes, D.N., Jimenez, A.R., Brindley, M.A. 2024. Chikungunya virus release is reduced by TIM-1 receptors through binding of envelope phosphatidylserine. J. Virol. 98, e0077524.

      9. Baranovich, T., Wong, S.-S., Armstrong, J., Marjuki, H., Webby, R.J., Webster, R.G., Govorkova, E.A. 2013. T-705 (Favipiravir) induces lethal mutagenesis in Influenza a H1N1 viruses in vitro. J. Virol. 87, 3741-3751.

      10. Battini, L., Fidalgo, D.M., Alvarez, D.E., Bollini, M. 2021. Discovery of a Potent and Selective Chikungunya virus envelope protein inhibitor through computer-aided drug design. ACS Infect. Dis. 7, 1503-1518.

      11. Battisti, V., Moesslacher, J., Abdelnabi, R., Leyssen, P., Rosales Rosas, A.L., Langendries, L., Aufy, M., Studenik, C., Kratz, J.M., Rollinger, J.M., Puerstinger, G., Neyts, J., Delang, L., Urban, E., Langer, T. 2024. Design, synthesis, and lead optimization of piperazinyl-pyrimidine analogues as potent small molecules targeting the viral capping machinery of Chikungunya virus. Eur. J. Med. Chem. 264, 116010.

      12. Bhutkar, M., Saha, A., Tomar, S. 2024. Viral methyltransferase inhibitors: berbamine, venetoclax, and ponatinib as efficacious antivirals against Chikungunya virus. Arch. Biochem. Biophys. 759, 110111.

      13. Castro, E.F., Alvarez, D.E. 2024. New highly selective antivirals for Chikungunya virus identified from the screening of a drug-like compound library. Curr.Microbiol. 81, 343.

      14. Cavalcanti, T.Y.V.d.L., Pereira, M.R., Paula, S.O.d., Franca, R.F.d.O. 2022. A review on Chikungunya virus epidemiology, pathogenesis and current vaccine development. Viruses 14, 969.

      15. Chen, M.W., Tan, Y.B., Zheng, J., Zhao, Y., Lim, B.T., Cornvik, T., Lescar, J., Ng, L.F.P., Luo, D. 2017. Chikungunya virus nsP4 RNA-dependent RNA polymerase core domain displays detergent-sensitive primer extension and terminal adenylyltransferase activities. Antiviral Res. 143, 38-47.

      16. Cheng, Y., Zheng, W., Dong, X., Sun, T., Xu, M., Xiang, L., Li, J., Wang, H., Jian, X., Yu, J., Li, P., Hu, T., Tian, G., Jiang, X., Zhang, L., Aisa, H.A., Xie, Y., Xiao, G., Shen, J. 2025. Design and development of a novel oral 4'-Fluorouridine double prodrug VV261 against SFTSV. J. Med. Chem. 68, 9811-9826.

      17. Ching, K.-C., Kam, Y.-W., Merits, A., Ng, L.F.P., Chai, C.L.L. 2015. Trisubstituted thieno[3,2-b]pyrrole 5-carboxamides as potent inhibitors of alphaviruses. J. Med. Chem. 58, 9196-9213.

      18. Ching, K.-C., Tran, T.N.Q., Amrun, S.N., Kam, Y.-W., Ng, L.F.P., Chai, C.L.L. 2017. Structural optimizations of thieno[3,2-b]pyrrole derivatives for the development of metabolically stable inhibitors of Chikungunya virus. J. Med. Chem. 60, 3165-3186.

      19. Costa, V.G.d., Saivish, M.V., Sinhorini, P.F., Nogueira, M.L., Rahal, P. 2024. A meta-analysis of Chikungunya virus in neurological disorders. Infect. Dis. Now. 54, 104938.

      20. Curtis, I.d., Simons, K. 1988. Dissection of Semliki Forest virus glycoprotein delivery from the trans-Golgi network to the cell surface in permeabilized BHK cells. Proc. Natl. Acad. Sci. U. S. A. 85, 8052-8056.

      21. Das, P.K., Puusepp, L., Varghese, F.S., Utt, A., Ahola, T., Kananovich, D.G., Lopp, M., Merits, A., Karelson, M. 2016. Design and validation of novel Chikungunya virus protease inhibitors. Antimicrob. Agents Chemother. 60, 7382-7395.

      22. de Souza, W.M., Lecuit, M., Weaver, S.C. 2025. Chikungunya virus and other emerging arthritogenic alphaviruses. Nat. Rev. Microbiol. 23, 585-601.

      23. Decroly, E., Ferron, F., Lescar, J., Canard, B. 2011. Conventional and unconventional mechanisms for capping viral mRNA. Nat. Rev. Microbiol. 10, 51-65.

      24. Delang, L., Li, C., Tas, A., Querat, G., Albulescu, I.C., De Burghgraeve, T., Guerrero, N.A.S., Gigante, A., Piorkowski, G., Decroly, E., Jochmans, D., Canard, B., Snijder, E.J., Perez-Perez, M.J., van Hemert, M.J., Coutard, B., Leyssen, P., Neyts, J. 2016. The viral capping enzyme nsP1: a novel target for the inhibition of chikungunya virus infection. Sci. Rep. 6, 31819.

      25. Delang, L., Segura Guerrero, N., Tas, A., Querat, G., Pastorino, B., Froeyen, M., Dallmeier, K., Jochmans, D., Herdewijn, P., Bello, F., Snijder, E.J., de Lamballerie, X., Martina, B., Neyts, J., van Hemert, M.J., Leyssen, P. 2014. Mutations in the Chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. J. Antimicrob. Chemother. 69, 2770-2784.

      26. Delmotte, P., Delmotte-Plaque, J. 1953. A new antifungal substance of fungal origin. Nature 171, 344.

      27. Delogu, I., Pastorino, B., Baronti, C., Nougairede, A., Bonnet, E., de Lamballerie, X. 2011. In vitro antiviral activity of arbidol against Chikungunya virus and characteristics of a selected resistant mutant. Antiviral Res. 90, 99-107.

      28. Di Mola, A., Peduto, A., La Gatta, A., Delang, L., Pastorino, B., Neyts, J., Leyssen, P., de Rosa, M., Filosa, R. 2014. Structure-activity relationship study of arbidol derivatives as inhibitors of chikungunya virus replication. Bioorg. Med. Chem. 22, 6014-6025.

      29. Ehteshami, M., Tao, S., Zandi, K., Hsiao, H.-M., Jiang, Y., Hammond, E., Amblard, F., Russell, O.O., Merits, A.,Schinazi, R.F. 2017. Characterization of β-d-N4-Hydroxycytidine as a novel inhibitor of Chikungunya virus. Antimicrob. Agents Chemother. 61, e02395-16.

      30. Fatma, B., Kumar, R., Singh, V.A., Nehul, S., Sharma, R., Kesari, P., Kuhn, R.J., Tomar, S. 2020. Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection. Antiviral Res. 179, 104808.

      31. FDA. 2023. FDA Approves First Vaccine to Prevent Disease Caused by Chikungunya Virus. https://www.fda.gov/news-events/press-announcements/fda-approves-first-vaccine-prevent-disease-caused-chikungunya-virus. (accessed 25 December 2025).

      32. FDA. 2025. FDA Update on the Safety of Ixchiq (Chikungunya vaccine, live).https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-update-safety-ixchiq-chikungunya-vaccine-live. (accessed 25 December 2025).

      33. Feferbaum-Leite, S., Marques Cassani, N., Aquino Ruiz, U.E., Clemente Dias, R.F., Nascimento Farago, D., Guevara-Vega, M., Nicolau-Junior, N., Sabino-Silva, R., Rezende Junior, C.d.O., Jardim, A.C.G. 2025. Benzothiazole derivatives as inhibitors of Chikungunya virus replicative cycle. Future Med. Chem. 17, 1105-1117.

      34. Feibelman, K.M., Fuller, B.P., Li, L., LaBarbera, D.V., Geiss, B.J. 2018. Identification of small molecule inhibitors of the Chikungunya virus nsP1 RNA capping enzyme. Antiviral Res. 154, 124-131.

      35. Ferreira, A.C., Reis, P.A., Freitas, C.S.d., Sacramento, C.Q., Hoelz, L.V.B., Bastos, M.M., Mattos, M., Rocha, N., Quintanilh, I.G.d.A., Pedrosa, C.d.S.G., Souza, L.R.Q., Loiola, E.C., Trindade, P., Vieira, Y.R., Barbosa-Lima, G., Neto, H.C.d.C.F., Boechat, N., Rehen, S.K., Bruning, K., Bozza, F.A., Bozza, P.T., Souza, T.M.L. 2018. Beyond members of the flaviviridae family, sofosbuvir also inhibits Chikungunya virus replication. Antimicrob. Agents Chemother. 63, e01389-01318.

      36. Freire, M.C.L.C., Basso, L.G.M., Mendes, L.F.S., Mesquita, N.C.M.R., Mottin, M., Fernandes, R.S., Policastro, L.R., Godoy, A.S., Santos, I.A., Ruiz, U.E.A., Caruso, I.P., Sousa, B.K.P., Jardim, A.C.G., Almeida, F.C.L., Gil, L.H.V.G., Andrade, C.H., Oliva, G. 2022. Characterization of the RNA-dependent RNA polymerase from Chikungunya virus and discovery of a novel ligand as a potential drug candidate. Sci. Rep. 12, 10601.

      37. Furuta, Y., Komeno, T., Nakamura, T. 2017. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jap. Acad., Ser. B Phys. Biol. Sci. 93, 449-463.

      38. Furuta, Y., Takahashi, K., Kuno-Maekawa, M., Sangawa, H., Uehara, S., Kozaki, K., Nomura, N., Egawa, H., Shiraki, K. 2005. Mechanism of action of T-705 against Influenza virus. Antimicrob. Agents Chemother. 49, 981-986.

      39. Ganeshpurkar, A., Gutti, G., Singh, S.K. 2019. RNA-dependent RNA polymerases and their emerging roles in antiviral therapy. In: Gupta, S.P. editor. Viral Polym. Academic Press., pp. 1-42.

      40. Garzan, A., Ahmed, S.K., Haese, N.N., Sulgey, G., Medica, S., Smith, J.L., Zhang, S., Ahmad, F., Karyakarte, S., Rasmussen, L., DeFilippis, V., Tekwani, B., Bostwick, R., Suto, M.J., Hirsch, A.J., Morrison, T.E., Heise, M.T., Augelli-Szafran, C.E., Streblow, D.N., Pathak, A.K., Moukha-Chafiq, O. 2024. 4-Substituted-2-thiazole amides as viral replication inhibitors of alphaviruses. J. Med. Chem. 67, 20858-20878.

      41. Gaur, M., Dash, R.N., Subudhi, B.B. 2026. Identification of sulfonamide drugs as allosteric inhibitor of Chikungunya virus envelope glycoprotein: an in silico approach for drug repurposing. Comput. Biol. Chem., 120, 108737.

      42. Ghildiyal, R., Gupta, S., Gabrani, R., Joshi, G., Gupta, A., Chaudhary, V.K., Gupta, V. 2019. In silico study of Chikungunya polymerase, a potential target for inhibitors. VirusDisease 30, 394-402.

      43. Ghoshal, A., Asressu, K.H., Hossain, M.A., Brown, P.J., Nandakumar, M., Vala, A., Merten, E.M., Sears, J.D., Law, I., Burdick, J.E., Morales, N.L., Perveen, S., Pearce, K.H., Popov, K.I., Moorman, N.J., Heise, M.T., Willson, T.M. 2024. Structure activity of β-amidomethyl vinyl sulfones as covalent inhibitors of Chikungunya nsP2 cysteine protease with antialphavirus activity. J. Med. Chem. 67, 16505-16532.

      44. Ghoshal, A., Sears, J.D., Hossain, M.A., Tse, E.G., Howell, S., Burdick, J.E., Morales, N.L., Martinez, S.A., Law, I., Streblow, Z.J., Streblow, D.N., Counago, R.M., Moorman, N.J., Heise, M.T., Willson, T.M. 2025. N-alkyl sulfamates as a new class of nsP2 cysteine protease inhibitors with broad-spectrum antialphaviral activity. J. Med. Chem. 68, 22918-22937.

      45. Gigante, A., Gomez-SanJuan, A., Delang, L., Li, C., Bueno, O., Gamo, A.-M., Priego, E.-M., Camarasa, M.-J., Jochmans, D., Leyssen, P., Decroly, E., Coutard, B., Querat, G., Neyts, J., Perez-Perez, M.-J. 2017. Antiviral activity of [1,2,3]triazolo[4,5- d ]pyrimidin-7(6 H )-ones against Chikungunya virus targeting the viral capping nsP1. Antiviral Res. 144, 216-222.

      46. Gomez-SanJuan, A., Gamo, A.-M., Delang, L., Perez-Sanchez, A., Amrun, S.N., Abdelnabi, R., Jacobs, S., Priego, E.-M., Camarasa, M.-J., Jochmans, D., Leyssen, P., Ng, L.F.P., Querat, G., Neyts, J., Perez-Perez, M.-J. 2018. Inhibition of the replication of different strains of Chikungunya virus by 3-aryl-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones. ACS Infect. Dis. 4, 605-619.

      47. Goncalves, W.A., de Sousa, C.D.F., Teixeira, M.M., Souza, D.G. 2025. A brief overview of Chikungunya-related pain. Eur. J. Pharmacol. 994, 177322.

      48. Hahn, C.S., Strauss, E.G., Strauss, J.H. 1985. Sequence analysis of three Sindbis virus mutants temperature-sensitive in the capsid protein autoprotease. Proc. Natl. Acad. Sci. U. S. A. 82, 4648-4652.

      49. Henry, M., Francis, L., Asin, V., Polson-Edwards, K., Olowokure, B. 2017. Chikungunya virus outbreak in Sint Maarten, 2013-2014. Rev. Panam. Salud Publica. 41, e61.

      50. Holmes, A.C., Basore, K., Fremont, D.H., Diamond, M.S. 2020. A molecular understanding of alphavirus entry. PLOS Pathog. 16, e1008876.

      51. Holmes, E.C., Tsetsarkin, K.A., Vanlandingham, D.L., McGee, C.E., Higgs, S. 2007. A single mutation in Chikungunya virus affects vector specificity and epidemic potential. PLOS Pathog. 3, e201.

      52. Islamuddin, M., Afzal, O., Khan, W.H., Hisamuddin, M., Altamimi, A.S.A., Husain, I., Kato, K., Alamri, M.A., Parveen, S. 2021. Inhibition of Chikungunya virus infection by 4-hydroxy-1-methyl-3-(3-morpholinopropanoyl)quinoline-2(1H)-one (QVIR) targeting nsP2 and E2 proteins. ACS Omega. 6, 9791-9803.

      53. Ivanova, L., Rausalu, K., Oseka, M., Kananovich, D.G., Zusinaite, E., Tammiku-Taul, J., Lopp, M., Merits, A., Karelson, M. 2021. Novel analogues of the Chikungunya virus protease inhibitor: molecular design, synthesis, and biological evaluation. ACS Omega. 6, 10884-10896.

      54. Ivanova, L., Rausalu, K., Zusinaite, E., Tammiku-Taul, J., Merits, A., Karelson, M. 2021. 1,3-thiazolbenzamide derivatives as Chikungunya virus nsP2 protease inhibitors. ACS Omega. 6, 5786-5794.

      55. Jadav, S.S., Sinha, B.N., Hilgenfeld, R., Pastorino, B., de Lamballerie, X., Jayaprakash, V. 2015. Thiazolidone derivatives as inhibitors of Cikungunya virus. Eur. J. Med. Chem. 89, 172-178.

      56. Jiang, X-y., Li, Jing., Wu, X-y, Zhan, P., Liu, X-y. 2020. Advances in Chikungunya virus inhibitors. Acta Pharm. Sin. 55, 754-762.

      57. Johansen, L.M., Brannan, J.M., Delos, S.E., Shoemaker, C.J., Stossel, A., Lear, C., Hoffstrom, B.G., DeWald, L.E., Schornberg, K.L., Scully, C., Lehar, J., Hensley, L.E., White, J.M., Olinger, G.G. 2013. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci. Transl. Med. 5, 108-120.

      58. Jones, R., Holmes, M., Reguera, N., Zamarreno, N., Arranz, R., Reguera, J. 2023. Structural basis and dynamics of Chikungunya alphavirus RNA capping by nsP1 capping pores. Proc. Natl. Acad. Sci. U. S. A. 120, e2213934120.

      59. Joyce, J., Snyder, J.E., Kuhn, R.J. 2009. A structural and functional perspective of alphavirus replication and assembly. Future microbiol. 4, 837-856.

      60. Kaduk, J.A., Gates-Rector, S., Blanton, T.N. 2023. Crystal structure of oxibendazole, C12H15N3O3. Powder Diffr. 38, 15-20.

      61. Karpe, Y.A., Aher, P.P., Lole, K.S. 2011. NTPase and 5'-RNA triphosphatase activities of Chikungunya virus nsP2 protein. PLoS ONE 6, e22336.

      62. Kaur, P., Thiruchelvan, M., Lee, R.C.H., Chen, H., Chen, K.C., Ng, M.L., Chu, J.J.H. 2013. Inhibition of Chikungunya virus replication by Harringtonine, a novel antiviral that suppresses viral protein expression. Antimicrob. Agents Chemother 57, 155-167.

      63. Kawashima, K.D., Suarez, L.-A.C., Labayo, H.K.M., Liles, V.R., Salvoza, N.C., Klinzing, D.C., Daroy, M.L.G., Matias, R.R., Natividad, F.F. 2014. Complete genome sequence of Chikungunya virus isolated in the Philippines. Genome Announc. 2, e00336-00314.

      64. Kielian, M., Chanel-Vos, C., Liao, M. 2010. Alphavirus entry and membrane fusion. Viruses, 2, 796-825.

      65. Kielian, M., Rey, F.A. 2006. Virus membrane-fusion proteins: more than one way to make a hairpin. Nat. Rev. Microbiol. 4, 67-76.

      66. Kovacikova, K., Gorostiola Gonzalez, M., Jones, R., Reguera, J., Gigante, A., Perez-Perez, M.-J., Purstinger, G., Moesslacher, J., Langer, T., Jeong, L.S., Delang, L., Neyts, J., Snijder, E.J., van Westen, G.J.P., van Hemert, M.J. 2021. Structural insights into the mechanisms of action of functionally distinct classes of Chikungunya virus nonstructural protein 1 inhibitors. Antimicrob. Agents Chemother. 65, e0256620.

      67. Kovacikova, K., Morren, B.M., Tas, A., Albulescu, I.C., van Rijswijk, R., Jarhad, D.B., Shin, Y.S., Jang, M.H., Kim, G., Lee, H.W., Jeong, L.S., Snijder, E.J., van Hemert, M.J. 2020. 6'-β-Fluoro-Homoaristeromycin and 6'-Fluoro-Homoneplanocin A are potent inhibitors of Chikungunya virus replication through their direct effect on viral nonstructural protein 1. Antimicrob. Agents Chemother. 64, e02532-19.

      68. Krummenacher, C., Aggarwal, M., Tapas, S., Preeti, Siwach, A., Kumar, P., Kuhn, R.J., Tomar, S. 2012. Crystal structure of Aura virus capsid protease and its complex with dioxane: New insights into capsid-glycoprotein molecular contacts. PLoS ONE 7, e51288.

      69. Kuhn, R.J., Gao, Y., Goonawardane, N., Ward, J., Tuplin, A., Harris, M. 2019. Multiple roles of the non-structural protein 3 (nsP3) alphavirus unique domain (AUD) during Chikungunya virus genome replication and transcription. PLOS Pathog. 15, e1007239.

      70. Kumar, R., Nehul, S., Singh, A., Tomar, S. 2021. Identification and evaluation of antiviral potential of thymoquinone, a natural compound targeting Chikungunya virus capsid protein. Virology 561, 36-46.

      71. Kumar, S., Subhadra, S., Pal, N., Pattnaik, R., Gosh, D. 2025. Challenges in diagnosis and control of Chikungunya virus infection: a review. Asian Pac. J. Trop. Med. 18, 431-442.

      72. Lahiri, H., Basu, K., Arkin, I.T. 2025. Ion-channel-targeting drugs for Chikungunya virus. Molecules, 30, 3942.

      73. Law, Y.-S., Utt, A., Tan, Y.B., Zheng, J., Wang, S., Chen, M.W., Griffin, P.R., Merits, A., Luo, D. 2019. Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase. Proc. Natl. Acad. Sci. U. S. A. 116, 9558-9567.

      74. Lani, R., Hassandarvish, P., Shu, M.-H., Phoon, W.H., Chu, J.J.H., Higgs, S., Vanlandingham, D., Bakar, S.A.,Zandi, K. 2016. Antiviral activity of selected flavonoids against Chikungunya virus. Antiviral Res. 133, 50-61.

      75. Li, J-y., Li, S., Zhong, W. 2025. Advances in anti-Chikungunya fever drugs. Chin. J. New Drugs, 34, 2378-2398.

      76. Li, L., Jose, J., Xiang, Y., Kuhn, R.J., Rossmann, M.G. 2010. Structural changes of envelope proteins during alphavirus fusion. Nature 468, 705-708.

      77. Lei, Q., Zhang, W., Geng, W., Jin, Z., Gan, X. 2025. Cinnamic acid derivatives in agrochemicals: current use and future perspective. J. Adv. Res. doi:10.1016/j.jare.2025.11.043.

      78. Li, S., Hu, X., Ahn, Y.-M., Medina, A., Ye, L., Heffner, A., Messing, S., Denson, J.-P., Esposito, D., Lee, E.M., Martinez, N.J. 2025. A quantitative high-throughput screening pipeline to identify small molecule inhibitors of Chikungunya nsP2 protease. Sci. Rep. 15, 33479.

      79. Lumsden, W.H.R. 1955. An epidemic of virus disease in Southern Province, Tanganyika territory, in 1952-1953 II. General description and epidemiology. Trans. R. Soc. Trop. Med. Hyg. 49, 33-57.

      80. Malet, H., Coutard, B., Jamal, S., Dutartre, H., Papageorgiou, N., Neuvonen, M., Ahola, T., Forrester, N., Gould, E.A., Lafitte, D., Ferron, F., Lescar, J., Gorbalenya, A.E., de Lamballerie, X., Canard, B. 2009. The crystal structures of Chikungunya and Venezuelan Equine Encephalitis virus nsP3 macro domains define a conserved adenosine binding pocket. J. Virol. 83, 6534-6545.

      81. Marques, E.T.A., Burke, D.S. 2025. Safety and immunogenicity of a virus-like particle Chikungunya virus vaccine. Lancet 405, 1314-1315.

      82. Marra, R.K.F., Kummerle, A.E., Guedes, G.P., Barros, C.d.S., Gomes, R.S.P., Cirne-Santos, C.C., Paixao, I.C.N.P., Neves, A.P. 2020. Quinolone-N-acylhydrazone hybrids as potent Zika and Chikungunya virus inhibitors. Bioorg. Med. Chem. Lett. 30, 126881.

      83. Mattila, S., Merilahti, P., Wazir, S., Quirin, T., Maksimainen, M.M., Zhang, Y., Xhaard, H., Lehtio, L., Ahola, T. 2021. Macrodomain binding compound MRS 2578 inhibits alphavirus replication. Antimicrob. Agents Chemother. 65, 01398-01321.

      84. Melton, J.V., Ewart, G.D., Weir, R.C., Board, P.G., Lee, E.,Gage, P.W. 2002. Alphavirus 6K proteins form ion channels. J. Biol. Chem. 277, 46923-46931.

      85. Merten, E.M., Sears, J.D., Leisner, T.M., Hardy, P.B., Ghoshal, A., Hossain, M.A., Asressu, K.H., Brown, P.J., Tse, E.G., Stashko, M.A., Li, K., Drouin, J.L.N., Herring, L.E., Mordant, A.L., Webb, T.S., Mills, C.A., Barker, N.K., Streblow, Z.J., Perveen, S., Arrowsmith, C.H., Counago, R.M., Arnold, J.J., Cameron, C.E., Streblow, D.N., Moorman, N.J., Heise, M.T., Willson, T.M., Popov, K.I., Pearce, K.H. 2024. Identification of a cell-active Chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach. Proc. Natl. Acad. Sci. U. S. A. 121, e2409166121.

      86. Metibemu, D.S., Adeyinka, O.S., Falode, J., Hampton, T., Crown, O., Ojobor, J.C., Narayanan, A., Julander, J., Ogungbe, I.V. 2024. Inhibitor of the non-structural protein 2 protease shows promising efficacy in mouse models of Chikungunya. Eur. J. Med. Chem. 278, 116808.

      87. Mishra, P., Kumar, A., Mamidi, P., Kumar, S., Basantray, I., Saswat, T., Das, I., Nayak, T.K., Chattopadhyay, S., Subudhi, B.B., Chattopadhyay, S. 2016. Inhibition of Chikungunya virus replication by 1-[(2-methylbenzimidazol-1-yl)methyl]-2-oxo-indolin-3-ylidene] amino] thiourea (MBZM-N-IBT). Sci. Rep., 6, 20122.

      88. Moesslacher, J., Battisti, V., Delang, L., Neyts, J., Abdelnabi, R., Purstinger, G., Urban, E., Langer, T. 2020. Identification of 2-(4-(phenylsulfonyl)piperazine-1-yl)pyrimidine analogues as novel inhibitors of Chikungunya virus. ACS Med. Chem. Lett. 11, 906-912.

      89. Montoya, M.C., Krysan, D.J. 2018. Repurposing estrogen receptor antagonists for the treatment of infectious disease. mBio 9, e02272-18.

      90. Mudgal, R., Bharadwaj, C., Dubey, A., Choudhary, S., Nagarajan, P., Aggarwal, M., Ratra, Y., Basak, S., Tomar, S. 2022. Selective estrogen receptor modulators limit alphavirus infection by targeting the viral capping enzyme nsP1. Antimicrob. Agents Chemother. 66, e01943-21.

      91. Mudgal, R., Mahajan, S., Tomar, S. 2019. Inhibition of Chikungunya virus by an adenosine analog targeting the SAM-dependent nsP1 methyltransferase. FEBS Lett. 594, 678-694.

      92. Murakami, Y., Fukasawa, M., Kaneko, Y., Suzuki, T., Wakita, T., Fukazawa, H. 2013. Selective estrogen receptor modulators inhibit hepatitis C virus infection at multiple steps of the virus life cycle. Microbes Infect. 15, 45-55.

      93. Muthu Ramalingam, B., Sears, J.D., Talbot, K.M., Su, Y.-W.N., Houliston, S., Hossain, M.A., Davis-Gilbert, Z.W., Zhao, C., Oh, H.J., Brown, P.J., Sanders, M.K., Moorman, S.R., Ojha, D., Burdick, J.E., Law, I., Morales, N.L., Martinez, S.A., Loppnau, P., Garcia Perez, J., Drobish, A.M., Morrison, T.E., Streblow, Z.J., Streblow, D.N., Arrowsmith, C.H., Vargason, A., Counago, R.M., Halabelian, L., Arnold, J.J., Cameron, C.E., Moorman, N.J., Heise, M.T., Willson, T.M. 2025. Identification of direct-acting nsP2 helicase inhibitors with antialphaviral activity. J. Med. Chem. 68, 14514-14536.

      94. Nainawat, K.S., Budakoti, A., Kumari, N., Verma, R.S., Gupta, A. 2025. Pharmaceutical perspectives of thymoquinone, a lead molecule from black cumin (Nigella sativa L.) with diverse biological targets. Food Chem. Adv. 8, 101053.

      95. Nam, S., Ga, Y.J., Lee, J.-Y., Hwang, W.-Y., Jung, E., Shin, J.s., Chen, W., Choi, G., Zhou, B., Yeh, J.-Y.,Go, Y.Y. 2021. Radicicol inhibits Chikungunya virus replication by targeting nonstructural protein-2. Antimicrob. Agents Chemother. 65, e00135-21.

      96. Narwal, M., Singh, H., Pratap, S., Malik, A., Kuhn, R.J., Kumar, P., Tomar, S. 2018. Crystal structure of chikungunya virus nsP2 cysteine protease reveals a putative flexible loop blocking its active site. Int. J. Biol. Macromol. 116, 451-462.

      97. Navarro, H., Scott, J.E., Smith, G.R., Ghiabi, P., Gibson, E., Loppnau, P., Harding, R.J., Hossain, M.A., Bose, M.R., Pearce, K.H., Merten, E.M., Willson, T.M., Brown, P.J. 2025. Identification of inhibitors of Chikungunya virus nsP2 ATPase. bioRxiv, doi:10.1101/2024.08.23.609196.

      98. Nguyen, P.T.V., Yu, H., Keller, P.A. 2015. Identification of Chikungunya virus nsP2 protease inhibitors using structure-base approaches. J. Mol. Graph. Model. 57, 1-8.

      99. Oliveira Lima, J.P., Alexandre Roberto, C.H., Nunes da Rocha, M., Moreira de Oliveira, V., Freire, R.M., Santos-Oliveira, R., Marinho, E.S., de Lima Neto, P., Almeida Fechine, P.B. 2025. Phenol and chromone compounds for in silico inhibition of nsP2 and nsP3 of Chikungunya virus. Pharm. Sci. Adv. 3, 100084.

      100. Pareek, A., Kumar, R., Mudgal, R., Neetu, N., Sharma, M., Kumar, P., Tomar, S. 2022. Alphavirus antivirals targeting RNA-dependent RNA polymerase domain of nsP4 divulged using surface plasmon resonance. FEBS J. 289, 4901-4924.

      101. Passos, G.F.S., Gomes, M.G.M., Aquino, T.M.d., Araujo-Junior, J.X.d., Souza, S.J.M.d., Cavalcante, J.P.M., Santos, E.C.d., Bassi, E.J., Silva-Junior, E.F.d. 2020. Computer-aided design, synthesis, and antiviral evaluation of novel acrylamides as potential inhibitors of E3-E2-E1 glycoproteins complex from Chikungunya virus. Pharmaceuticals 13, 141.

      102. Pialoux, G., Gauzere, B.-A., Jaureguiberry, S., Strobel, M. 2007. Chikungunya, an epidemic arbovirosis. Lancet Infect. Dis. 7, 319-327.

      103. Pohjala, L., Utt, A., Varjak, M., Lulla, A., Merits, A., Ahola, T., Tammela, P. 2017. Inhibitors of alphavirus entry and replication identified with a stable Chikungunya replicon cell line and virus-based assays. PLoS ONE 6, e28923.

      104. Priya, T.S., Patil, P., Siva, B., Roy, D., Dhote, R., Parashar, D., Alagarasu, K., Cherian, S., Suresh Babu, K. 2025. Novel α-mangostin derivatives as promising antiviral agents: isolation, synthesis, and evaluation against chikungunya virus. Eur. J. Med. Chem. 284, 117227.

      105. Puranik, N.V., Rani, R., Singh, V.A., Tomar, S., Puntambekar, H.M., Srivastava, P. 2019. Evaluation of the antiviral potential of halogenated dihydrorugosaflavonoids and molecular modeling with nsP3 protein of Chikungunya virus (CHIKV). ACS Omega 4, 20335-20345.

      106. Rabelo, V.W., Sanchez-Nunez, M.L., Correa-Amorim, L.S., Kuhn, R.J., Abreu, P.A., Paixao, I.C.N.P. 2024. In silico drug repurposing uncovered the antiviral potential of the antiparasitic drug oxibendazole against the Chikungunya virus. ACS Omega 9, 27632-27642.

      107. Rafidah, L., Pouya, H., Wei, C.C., Ehsan, M., Hann, C.J.J., Kai, R., Andres, M., Stephen, H., Dana, V., Sazaly, A.B., Keivan, Z. 2015. Antiviral activity of silymarin against Chikungunya virus. Sci. Rep. 5, 11421.

      108. Rashad, A.A., Keller, P.A. 2013. Structure based design towards the identification of novel binding sites and inhibitors for the Chikungunya virus envelope proteins. J. Mol. Graph. Model. 44, 241-252.

      109. Rathore, A., Sharma, K.B., Subramani, C., Ganesh, K., Sharma, A., Basu, B., Balyan, S., Sharma, G., Ka, S., Deb, A., Srivastava, M., Chugh, S., Sehrawat, S., Bharadwaj, K., Rout, A., Sahoo, P.K., Saurav, S., Motiani, R.K., Singh, R., Jain, D., Asthana, S., Wadhwa, R., Vrati, S. 2024. Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection. PLOS Pathog. 20, e1012816.

      110. Reis, E.V.S., Damas, B.M., Mendonca, D.C., Bonjardim, J.S.C.A. 2021. In-depth characterization of the Chikungunya virus replication cycle. J. Virol. 96, JVI0173221.

      111. Reyes-Gastellou, A., Jimenez-Alberto, A., Castelan-Vega, J.A., Aparicio-Ozores, G., Ribas-Aparicio, R.M. 2021. Chikungunya nsP4 homology modeling reveals a common motif with Zika and Dengue RNA polymerases as a potential therapeutic target. J. Mol. Model. 27, 247.

      112. Rezza, G., Nicoletti, L., Angelini, R., Romi, R., Finarelli, A.C., Panning, M., Cordioli, P., Fortuna, C., Boros, S., Magurano, F., Silvi, G., Angelini, P., Dottori, M., Ciufolini, M.G., Majori, G.C., Cassone, A. 2007. Infection with Chikungunya virus in Italy: an outbreak in a temperate region. Lancet 370, 1840-1846.

      113. Roach, C.M., Streblow, Z.J., Zhang, Y., Ogorek, T.J., Flores, A.P., Jonsson, C.B., Streblow, D.N., Golden, J.E. 2025. Restructuring antiviral quinazolinone frameworks to derive and optimize inhibitors of Chikungunya virus. ACS Med. Chem. Lett. 16, 2320-2327.

      114. Roques, P., Bullard-Feibelman, K.M., Fuller, B.P., Geiss, B.J. 2016. A sensitive and robust high-throughput screening assay for inhibitors of the Chikungunya virus nsP1 capping enzyme. PLoS ONE 11, e0158923.

      115. Russo, A.T., White, M.A., Watowich, S.J. 2006. The crystal structure of the Venezuelan equine encephalitis alphavirus nsP2 protease. Structure 14, 1449-1458.

      116. Saha, A., Acharya, B.N., Parida, M., Saxena, N., Rajaiya, J., Dash, P.K. 2023. Identification of 2,4-diaminoquinazoline derivative as a potential small-molecule inhibitor against Chikungunya and Ross River viruses. Viruses 15, 2194.

      117. Saha, A., Acharya, B.N., Priya, R., Tripathi, N.K., Shrivastava, A., Rao, M.K., Kesari, P., Narwal, M., Tomar, S., Bhagyawant, S.S., Parida, M., Dash, P.K. 2018. Development of nsP2 protease based cell free high throughput screening assay for evaluation of inhibitors against emerging Chikungunya virus. Sci. Rep. 8, 1-13.

      118. Saijo, T., Jagdish, R., Lijo, J., Stephan, S., M, P.B., Ottmar, H. 2013. Chikungunya virus capsid protein contains nuclear import and export signals. Virol. J. 10, 269.

      119. Saikat, D., Soumyajit, G., Suman, K.S., Chandan, M., Chinmayee, M., Ankeeta, G., Prabhudutta, M., Ankita, D., Smita, P.S., Dileep, V., Kant, B.T., Subhasis, C., Bhusan, S.B., Soma, C. 2022. MBZM-N-IBT, a novel small molecule, restricts Chikungunya virus infection by targeting nsP2 protease activity In vitro, In vivo, and ex vivo. Antimicrob. Agents Chemother. 66, e0046322.

      120. Sam, I.C., Chan, Y.F., Chan, S.Y., Loong, S.K., Chin, H.K., Hooi, P.S., Ganeswrie, R., AbuBakar, S. 2009. Chikungunya virus of Asian and Central/East African genotypes in Malaysia. J. Clin. Virol., 46, 180-183.

      121. Samy, A.M., Dey, D., Siddiqui, S.I., Mamidi, P., Ghosh, S., Kumar, C.S., Chattopadhyay, S., Ghosh, S., Banerjee, M. 2019. The effect of amantadine on an ion channel protein from Chikungunya virus. PLOS Negl. Trop. Dis. 13, e0007548.

      122. Sanchez, J.S., Canon, A.M., Lombo, J.C. 2019. Sintomas subagudos y cronicos de la fiebre de chikungunya en un grupo de personas adultas en Ibague, Colombia. Biomedica 39, 587-594.

      123. Sawada, S., Yoshikawa, M., Tsutsui, K., Miyazaki, T., Kano, K., MishiroSato, E., Tsukiji, S. 2023. Palmitoylation-dependent small-molecule fluorescent probes for live-cell golgi imaging. ACS Chem. Biol. 18, 1200-1207.

      124. Schuffenecker, I., Iteman, I., Michault, A., Murri, S., Frangeul, L., Vaney, M.-C., Lavenir, R., Pardigon, N., Reynes, J.-M., Pettinelli, F., Biscornet, L., Diancourt, L., Michel, S., Duquerroy, S., Guigon, G., Frenkiel, M.-P., Brehin, A.-C., Cubito, N., Despres, P., Kunst, F., Rey, F.A., Zeller, H., Brisse, S. 2006. Genome microevolution of Chikungunya viruses causing the Indian Ocean outbreak. PLoS Med. 3, e263.

      125. Scuotto, M., Abdelnabi, R., Collarile, S., Schiraldi, C., Delang, L., Massa, A., Ferla, S., Brancale, A., Leyssen, P., Neyts, J., Filosa, R. 2017. Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of Chikungunya virus replication. Bioorg. Med. Chem. 25, 327-337.

      126. Sears, J.D., Popov, K.I., Sylvester, P., Dickmander, R., Diaz, J.L., Chang, C.K., Huff, J., Sanders, W., Saba, N.A., Sorensen, M., Drobish, A.M., May, N.A., Namitz, K., Fecko, J., Yennawar, N.H., Morrison, T.E., Tropsha, A., Heise, M.T.,Moorman, N.J. 2025. Novel computational pipeline to identify target sites for broad spectrum antiviral drugs. Antiviral Res. 245, 106322.

      127. Setyawati, I., Setiawan, A.G., Nemchinova, M.,Vidilaseris, K. 2024. The potential inhibitory mechanism of EGCG against the Chikungunya virus targeting non-structural protein 2 through molecular dynamics simulation. Sci. Rep. 14, 29797.

      128. Shin, Y.S., Jarhad, D.B., Jang, M.H., Kovacikova, K., Kim, G., Yoon, J.-s., Kim, H.-R., Hyun, Y.E., Tipnis, A.S., Chang, T.-S., van Hemert, M.J., Jeong, L.S. 2020. Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of Chikungunya virus replication. Eur. J. Med. Chem. 187, 111956.

      129. Simon-Djamel, T., Veronique, B., Jean, G., Fabrice, S., Antoine, F., Xavier, d.L. 2013. Chikungunya fever: a clinical and virological investigation of outpatients on Reunion Island, South-West Indian Ocean. PLoS negl. Trop. Dis. 7, e2004.

      130. Simon, F., Javelle, E., Cabie, A., Bouquillard, E., Troisgros, O., Gentile, G., Leparc-Goffart, I., Hoen, B., Gandjbakhch, F., Rene-Corail, P., Franco, J.M., Caumes, E., Combe, B., Poiraudeau, S., Gane-Troplent, F., Djossou, F., Schaerverbeke, T., Criquet-Hayot, A., Carrere, P., Malvy, D., Gaillard, P., Wendling, D. 2015. French guidelines for the management of Chikungunya (acute and persistent presentations). November 2014. Med. Mal. Infect. 45, 243-263.

      131. Simon, F., Parola, P., Grandadam, M., Fourcade, S., Oliver, M., Brouqui, P., Hance, P., Kraemer, P., Mohamed, A.A., de Lamballerie, X., Charrel, R., Tolou, H. 2007. Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. Medicine 86, 123-137.

      132. Simone, B., Lienert, F. 2025. Post-authorisation experience and reported adverse events following use of a virus-like particle Chikungunya vaccine, United States and Germany, up to August 2025. Euro. Surveill., 30, 2500792.

      133. Singh, S.K., Schilte, C., Staikovsky, F., Couderc, T., Madec, Y., Carpentier, F., Kassab, S., Albert, M.L., Lecuit, M.,Michault, A. 2013. Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study. PLOS Negl. Trop. Dis. 7, e2137.

      134. Solignat, M., Gay, B., Higgs, S., Briant, L., Devaux, C. 2009. Replication cycle of Chikungunya: a re-emerging arbovirus. Virology 393, 183-197.

      135. Souza, B.G.d., Choudhary, S., Vilela, G.G., Passos, G.F.S., Costa, C.A.C.B., Freitas, J.D.d., Coelho, G.L., Brandao, J.d.A., Anderson, L., Bassi, E.J., Araujo-Junior, J.X.d., Tomar, S., Silva-Junior, E.F.d. 2023. Design, synthesis, antiviral evaluation, and In silico studies of acrylamides targeting nsP2 from Chikungunya virus. Eur. J. Med. Chem. 258, 115572.

      136. Strauss, E.G., De Groot, R.J., Levinson, R., Strauss, J.H. 1992. Identification of the active site residues in the nsP2 proteinase of Sindbis virus. Virology 191, 932-940.

      137. Tan, Y.B., Lello, Laura S., Liu, X., Law, Y.-S., Kang, C., Lescar, J., Zheng, J., Merits, A., Luo, D. 2022. Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold. Nucleic Acids Res. 50, 1000-1016.

      138. Temizer Keser, A.B., Gungor, G., Kaptein, S., Jochmans, D., Ozbil, M., Kaynak, F.B., Neyts, J., Karali, N. 2026. New spirooxindole-benzothiazole hybrids incorporating a trifluoromethyl moiety as antiviral agents: Design, synthesis, crystal structure analysis, and in silico studies. J. Mol. Struct. 1351, 144093.

      139. Teppor, M., Zusinaite, E., Merits, A., Heise, M.T. 2021. Phosphorylation sites in the hypervariable domain in Chikungunya virus nsP3 are crucial for viral replication. J. Virol. 95, e02276-20.

      140. Tiawsirisup, S. 2011. Chikungunya virus in Thailand; an update. Thai J. Vet. Med., 41, 133-134.

      141. Tindale, L.C., Richardson, J.S., Anderson, D.M., Mendy, J., Muhammad, S., Loreth, T., Tredo, S.R., Ramanathan, R., Jenkins, V.A., Bedell, L., Ajiboye, P. 2025. Chikungunya virus virus-like particle vaccine safety and immunogenicity in adults older than 65 years: a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 405, 1353-1361.

      142. Tohma, D., Tajima, S., Kato, F., Sato, H., Kakisaka, M., Hishiki, T., Kataoka, M., Takeyama, H., Lim, C.K., Aida, Y., Saijo, M. 2019. An estrogen antagonist, cyclofenil, has anti-dengue-virus activity. Arch. Virol. 164, 225-234.

      143. Tripathi, P.K., Soni, A., Singh Yadav, S.P., Kumar, A., Gaurav, N., Raghavendhar, S., Sharma, P., Sunil, S., Ashish, Jayaram, B., Patel, A.K. 2020. Evaluation of novobiocin and telmisartan for anti-CHIKV activity. Virology 548, 250-260.

      144. Tsetsarkin, K.A., Chen, R., Sherman, M.B., Weaver, S.C. 2011. Chikungunya virus: evolution and genetic determinants of emergence. Curr. Opin. Virol. 1, 310-317.

      145. Verma, J., Hasan, A., Sunil, S., Subbarao, N. 2022. In silico identification and in vitro antiviral validation of potential inhibitors against Chikungunya virus. J. Comput.-Aided Mol. Des. 36, 521-536.

      146. Verwimp, S., Wagoner, J., Arenas, E.G., Coninck, L.D., Abdelnabi, R., Hyde, J.L., Schiffer, J.T., White, J.M., Matthijnssens, J., Neyts, J., Polyak, S.J., Delang, L. 2025. Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo. Antiviral Res. 239, 106186.

      147. Wada, Y., Orba, Y., Sasaki, M., Kobayashi, S., Carr, M.J., Nobori, H., Sato, A., Hall, W.W., Sawa, H. 2017. Discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsP4) of chikungunya virus. Virology 505, 102-112.

      148. Wahid, B., Ali, A., Rafique, S., Idrees, M. 2017. Global expansion of Chikungunya virus: mapping the 64-year history. Int. J. Infect. Dis., 58, 69-76.

      149. Wang, J., Grishin, A.V., Ford, H.R. 2016. Experimental anti-inflammatory drug semapimod inhibits TLR signaling by targeting the TLR chaperone gp96. J. Immunol. 196, 5130-5137.

      150. Wang, J., Zhang, L. 2025. The Chikungunya virus outbreak in Foshan, China: a rising public health threat in tropical and subtropical regions. J. Infect. 91, 106591.

      151. Wang, M., Wang, L., Leng, P., Guo, J., Zhou, H. 2024. Drugs targeting structural and nonstructural proteins of the Chikungunya virus: a review. Int. J. Biol. Macromol. 262, 129949.

      152. Weber, C., Sliva, K., von Rhein, C., Kummerer, B.M., Schnierle, B.S. 2015. The green tea catechin, epigallocatechin gallate inhibits Chikungunya virus infection. Antiviral Res. 113, 1-3.

      153. WHO. 2025. Chikungunya epidemiology update - June 2025. https://www.who.int/publications/m/item/chikungunya-epidemiology-update-june-2025. (Accessed 25 December 2025).

      154. Wolfe, M.S., Borchardt, R.T. 1991. S-adenosyl-L-homocysteine hydrolase as a target for antiviral chemotherapy. J. Med. Chem. 34, 1521-1530.

      155. Wu, S.-R., Haag, L., Sjoberg, M., Garoff, H., Hammar, L. 2008. The dynamic envelope of a fusion class II virus. J. Biol. Chem. 283, 26452-26460.

      156. Yactayo, S., Staples, J.E., Millot, V., Cibrelus, L., Ramon-Pardo, P. 2016. Epidemiology of Chikungunya in the Americas. J. Infect. Dis. 214, S441-S445.

      157. Yergolkar, P.N., Tandale, B.V., Arankalle, V.A., Sathe, P.S., Sudeep, A.B., Gandhe, S.S., Gokhle, M.D., Jacob, G.P., Hundekar, S.L., Mishra, A.C. 2006. Chikungunya outbreaks caused by African genotype, India. Emerg. Infect. Dis. 12, 1580-1583.

      158. Yien, L.M.C., Kuo, Z., Bia, T.Y., Mai, N.T., Dahai, L. 2023. Chikungunya virus non-structural protein 1 is a versatile RNA capping and decapping enzyme. J. Biol. Chem. 299, 105415.

      159. Yin, P., Boyce, R., Wang, S., Sirrine, M., Leach, A., Chu, D., Vyshenska, D., Sahin, Z., Wong, J., Moore, T., Lewis, D.S.M., Pelly, S.C., Liotta, D., Merits, A., Greninger, A.L., Plemper, R.K., Kielian, M., Cox, R.M. 2025. Identification and characterization of novel Chikungunya virus polymerase inhibitors. J. Virol. 100, e00305-26.

      160. Yoon, J.-s., Kim, G., Jarhad, D.B., Kim, H.-R., Shin, Y.-S., Qu, S., Sahu, P.K., Kim, H.O., Lee, H.W., Wang, S.B., Kong, Y.J., Chang, T.-S., Ogando, N.S., Kovacikova, K., Snijder, E.J., Posthuma, C.C., van Hemert, M.J., Jeong, L.S. 2019. Design, synthesis, and anti-RNA virus activity of 6′-fluorinated-aristeromycin analogues. J. Med. Chem. 62, 6346-6362.

      161. Zhang, X., Jia, D., Liu, H., Zhu, N., Zhang, W., Feng, J., Yin, J., Hao, B., Cui, D., Deng, Y., Xie, D., He, L., Li, B. 2017. Identification of 5-Iodotubercidin as a genotoxic drug with anti-cancer potential. PLoS ONE 8, e62527.

      162. Zhang, X.X., Garzan, A., Haese, N.N., Bostwick, R., Martinez, Y., Rasmussen, L., Streblow, D.N., Heise, M.T., Pathak, A.K., Augelli-Szafran, C.E., Wu, M. 2021. Pyrimidone inhibitors targeting Chikungunya virus nsP3 macrodomain by fragment-based drug design. PLoS ONE 16, e0245013.

      163. Zhang, Y., Tang, S., Chen, L., Song, S., Cao, J., Tian, G., Xiao, G., Shen, J., Zhang, L. 2026. Investigation of a clinical trial drug VV261 as a potent antiviral candidate against Chikungunya virus. Signal Transduct. Target Ther. 11, 56.

      164. Zheng, Z., Ji, H., Shan, Z., Xu, J., Li, J., Zhang, X., Zheng, J., Jiang, S., Zhang, N. 2026. Chikungunya in 2025: Comprehensive Insights into Virology, Diagnostics, Vaccines, and Antiviral Therapies. Viruses 18, 100.

    • 加载中

    Figures(1)

    PDF

    Article Metrics

    Article views(23) PDF downloads(0) Cited by()

    Related
    Proportional views

      Recent progress in anti-Chikungunya virus drug discovery: Focus on the viral life cycle and direct-acting antivirals

        Corresponding author: Leike Zhang, zhangleike@wh.iov.cn
        Corresponding author: Bin Lin, blin@syphu.edu.cn
        Corresponding author: Xiangrui Jiang, jiangxiangrui@simm.ac.cn
      • a. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;
      • b. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China;
      • c. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
      • d. School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei 230012, China;
      • e. Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
      • f. University of Chinese Academy of Sciences, Beijing 100049, China
      • Received Date: 28 February 2026
      • Accepted Date: 03 July 2026

      Abstract: Chikungunya virus (CHIKV) belongs to the genus Alphavirus of the family Togaviridae. CHIKV infection generally causes severe clinical symptoms, including debilitating arthralgia, fever, hemorrhage and cutaneous rashes. In recent years, the transmission range of CHIKV has continued to expand, resulting in recurrent local outbreaks in densely populated and economically developed regions and posing a severe threat to public health. Accordingly, safe and effective anti-CHIKV therapeutics are urgently needed for the clinical treatment of infected patients. Nevertheless, no specific anti-CHIKV drugs have been approved for clinical use or advanced into clinical trials, and relevant research and development remain confined to the preclinical stage. This review systematically illustrates the key steps of the CHIKV life cycle, core viral components and vital functional domains, and summarizes the current research progress of anti-CHIKV agents. It comprehensively outlines the discovery strategies, structural optimization directions and activity evaluation approaches of anti-CHIKV small-molecule compounds, and further investigates their action targets. Notably, nsP2 and nsP4 represent promising targets for broad-spectrum anti-CHIKV even anti-alphavirus drug development due to their structural conservation across alphavirus species and druggable features. This work provides a solid theoretical basis and valuable reference for the future research and development of novel anti-CHIKV drugs.

        HTML

      Figure (1)  Reference (164) Relative (20)

      目录

      This journal is a member of, and subscribes to the principles of, the Committee on Publication Ethics (COPE)

      鄂ICP备05001977号

         

      鄂公网安备 42010602003674号

      Copyright © 2019 Virologica Sinica. All rights reserved

      /

      DownLoad:  Full-Size Img  PowerPoint
      Return
      Return