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Título: | Antivirals Against Chikungunya Virus: Analyzing the Current Situation to Identify New Opportunities |
Autor: | Peréz-Pérez, María-Jesús CSIC ORCID | Fecha de publicación: | 29-ago-2021 | Resumen: | Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted to humans by the bites of infected Aedes mosquitos. The morbidity associated to CHIKV infections, with million of cases in tropical and subtropical areas, has an increasing impact on health with important social and economic consequences. Large phenotypic screening campaigns and drug repurposing approaches have identified active compounds against CHIKV replication, in a few cases reaching clinical trials, although no drug has been approved yet.1 Fortunately, our knowledge at the structural level and at the functional role of some of the clue non-structural proteins required for viral replication is increasing in the latest two years. Also significant advances are being performed in clarifying the interactions of the virus with the host. Our research group, in close collaboration with different partners, has described 3-aryl-triazolo[3,4-d]pyrimidines as the first nsP1 inhibitors of CHIKV.2¿4 The viral nsP1 possess methyltransferase (MTase) and guanylyltransferase (GTase) activities required for the 5¿-capping of the nascent mRNAs, a crucial step for viral replication.5 Very recently, it has been shown that nsP1 is highly palmitoylated and serves as the anchoring of the replication complex to cellular membranes.6 Indeed CHIKV infection remodelates the plasma membrane creating invaginations known as spherules, where the new RNA is synthesized. Also very recently, the cryo-EM structure of CHIKV nsP1 has been described, showing its assembly in a dodecameric ring, where the ring shape favors the exit of the capped mRNA.7 These important advances related to nsP1 open new opportunities for antiviral intervention. Ref (1) Pérez-Pérez, M. J.; Delang, L.; Ng, L. F. P.; et al. Expert Opin. Drug Discov. 2019, 14, 855¿866. https://doi.org/10.1080/17460441.2019.1629413. (2) Gómez-SanJuan, A.; Gamo, A.-M.; Delang, L.; et al. ACS Infect. Dis. 2018, 4, 605¿619. https://doi.org/10.1021/acsinfecdis.7b00219. (3) Gigante, A.; Gómez-SanJuan, A.; Delang, L.; et al. Antiviral Res. 2017, 144, 216¿222. https://doi.org/10.1016/j.antiviral.2017.06.003. (4) Gigante, A.; Canela, M.-D.; Delang, L.;et al. J. Med. Chem. 2014, 57, 4000¿4008. https://doi.org/10.1021/jm401844c. (5) Delang, L.; Li, C.; Tas, A.; et al.. Sci. Rep. 2016, 6, 31819. https://doi.org/10.1038/srep31819. (6) Bakhache, W.; Neyret, A.; Bernard, E et al. J. Virol. 2020, 94, 1¿20. https://doi.org/10.1128/JVI.02183-19. (7) Jones, R.; Bragagnolo, G.; Arranz, R.; Reguera, J. Nature 2021, 589, 615¿619. https://doi.org/10.1038/s41586-020-3036-8. | URI: | http://hdl.handle.net/10261/262782 |
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