Artículo
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Piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. In vitro antiviral activity evaluation against Zika and Dengue viruses
Autor/es | García Lozano, María del Rosario
Dragoni, Filippo Gallego, Paloma Mazzotta, Sarah López Gómez, Alejandro Boccuto, Adele Martínez-Cortés, Carlos Rodríguez-Martínez, Alejandro Pérez-Sánchez, Horacio Vega Pérez, José Manuel ![]() ![]() ![]() ![]() ![]() ![]() ![]() Del Campo, José Antonio Vicenti, Ilaria Vega Holm, Margarita ![]() ![]() ![]() ![]() ![]() ![]() ![]() Iglesias Guerra, Fernando ![]() ![]() ![]() ![]() ![]() ![]() |
Departamento | Universidad de Sevilla. Departamento de Química Orgánica y Farmacéutica |
Fecha de publicación | 2023 |
Fecha de depósito | 2023-02-22 |
Publicado en |
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Premios | Premio Mensual Publicación Científica Destacada de la US. Facultad de Farmacia |
Resumen | Since 2011 Direct Acting antivirals (DAAs) drugs targeting different non-structural (NS) viral proteins (NS3, NS5A or NS5B inhibitors) have been approved for clinical use in HCV therapies. However, currently there are not ... Since 2011 Direct Acting antivirals (DAAs) drugs targeting different non-structural (NS) viral proteins (NS3, NS5A or NS5B inhibitors) have been approved for clinical use in HCV therapies. However, currently there are not licensed therapeutics to treat Flavivirus infections and the only licensed DENV vaccine, Dengvaxia, is restricted to patients with preexisting DENV immunity. Similarly to NS5 polymerase, the NS3 catalytic region is evolutionarily conserved among the Flaviviridae family sharing strong structural similarity with other proteases belonging to this family and therefore is an attractive target for the development of pan-flavivirus therapeutics. In this work we present a library of 34 piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. The library was developed through a privileged structures-based design and then biologically screened using a live virus phenotypic assay to determine the half-maximal inhibitor concentration (IC50) of each compound against ZIKV and DENV. Two lead compounds, 42 and 44, with promising broad-spectrum activity against ZIKV (IC50 6.6 µM and 1.9 µM respectively) and DENV (IC50 6.7 µM and 1.4 µM respectively) and a good security profile were identified. Besides, molecular docking calculations were performed to provide insights about key interactions with residues in NS3 proteases’ active sites. |
Agencias financiadoras | Ministerio de Ciencia, Innovación y Universidades (MICINN). España Ministerio de Economía y Competitividad (MINECO). España |
Identificador del proyecto | PID2019-104767RB-I00
![]() PI19/00589 ![]() PI19/ 01404 ![]() PI16/01842 ![]() PI17/00535 ![]() GLD19/00100 ![]() |
Cita | García Lozano, M.d.R., Dragoni, F., Gallego, P., Mazzotta, S., López Gómez, A., Boccuto, A.,...,Iglesias Guerra, F. (2023). Piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. In vitro antiviral activity evaluation against Zika and Dengue viruses. Bioorganic Chemistry, 133, 106408. https://doi.org/10.1016/j.bioorg.2023.106408. |
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