Piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. In vitro antiviral activity evaluation against Zika and Dengue viruses

Autor:	María del Rosario García-Lozano, Filippo Dragoni, Paloma Gallego, Sarah Mazzotta, Alejandro López-Gómez, Adele Boccuto, Carlos Martínez-Cortés, Alejandro Rodríguez-Martínez, Horacio Pérez-Sánchez, José Manuel Vega-Pérez, José Antonio Del Campo, Ilaria Vicenti, Margarita Vega-Holm, Fernando Iglesias-Guerra
Přispěvatelé:	Universidad de Sevilla. Departamento de Química Orgánica y Farmacéutica, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Ministerio de Economía y Competitividad (MINECO). España
Rok vydání:	2023
Předmět:	Small molecules inhibitors Live virus phenotypic assay Flavivirus Molecular docking Organic Chemistry Drug Discovery Acyl and urea piperazine derivatives Privileged structures Molecular modeling Molecular Biology Biochemistry NS3 protease
Zdroj:	Bioorganic Chemistry. 133:106408
ISSN:	0045-2068
DOI:	10.1016/j.bioorg.2023.106408
Popis:	This work has been supported by Ministerio de Ciencia, Innovación y Universidades, Plan Estatal 2017-2020 Retos - Proyectos I + D + i (PID2019-104767RB-I00). MRGL also thanks Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (grants PI19/00589, PI19/01404, PI16/01842, PI17/00535 and GLD19/00100) for financial support. This work was supported by funds from MIUR Ministero dell’Istruzione, dell’Università della Ricerca Italiano, project PRIN 2017, ORIGINALE CHEMIAE in Antiviral Strategy—Origin and Modernization of Multi-Component Chemistry as a Source of Innovative Broad-Spectrum Antiviral Strategy (cod. 2017BMK8JR) and from Tuscany region, project Tuscany Antiviral Research Network -TUSCAVIR.NET (Bando Ricerca Salute 2018). We would like to thank Giulietta Venturi for making the ZIKV H/PF/2013 strain available for this study. This work has also been funded by the Fundación Séneca de la Región de Murcia under Project 20988/PI/18. This research was partially supported by the computer resources and the technical support provided by the supercomputing infrastructure of the NLHPC (ECM-02), Powered@NLHPC and the Extremadura Research Centre for Advanced Technologies (CETA − CIEMAT), funded by the European Regional Development Fund (ERDF). CETA − CIEMAT is part of CIEMAT and the Government of Spain. Authors thank CITIUS (Centro de Investigación, Tecnología e Innovación de la Universidad de Sevilla) for its important contribution in recording NMR and Mass spectra and in elemental analysis determination. Supplementary data to this article can be found online at https://doi.org/10.1016/j.bioorg.2023.106408 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. Ministerio de Ciencia, Innovacion y Universidades, Plan Estatal 2017-2020 Retos-Proyectos I + D + i (PID2019-104767RB-I00) Spanish Government PI19/00589 PI19/01404 PI16/01842 PI17/00535 GLD19/00100 MIUR Ministero dell'Istruzione, dell'Universita della Ricerca Italiano, project PRIN 2017, ORIGINALE CHEMIAE in Antiviral Strategy-Origin and Modernization of Multi-Component Chemistry as a Source of Innovative Broad-Spectrum Antiviral Strategy 2017BMK8JR Tuscany region, project Tuscany Antiviral Research Network-TUSCAVIR.NET (Bando Ricerca Salute 2018) Fundación Séneca 20988/PI/18 NLHPC ECM-02 European Commission
Databáze:	OpenAIRE
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