@misc{10481/81350,
year = {2023},
month = {2},
url = {https://hdl.handle.net/10481/81350},
abstract = {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.},
organization = {Ministerio de Ciencia, Innovacion y Universidades, Plan Estatal 2017-2020 Retos-Proyectos I + D + i (PID2019-104767RB-I00)},
organization = {Spanish Government 	PI19/00589 	PI19/01404 	PI16/01842 	PI17/00535 	GLD19/00100},
organization = {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},
organization = {Tuscany region, project Tuscany Antiviral Research Network-TUSCAVIR.NET (Bando Ricerca Salute 2018)},
organization = {Fundación Séneca 20988/PI/18},
organization = {NLHPC ECM-02},
organization = {European Commission},
publisher = {Elsevier},
keywords = {Flavivirus},
keywords = {NS3 protease},
keywords = {Small molecules inhibitors},
keywords = {Privileged structures},
keywords = {Acyl and urea piperazine derivatives},
keywords = {Live virus phenotypic assay},
keywords = {Molecular docking},
keywords = {Molecular modeling},
title = {Piperazine-derived small molecules as potential Flaviviridae NS3 protease  inhibitors. In vitro antiviral activity evaluation against Zika and  Dengue viruses},
doi = {10.1016/j.bioorg.2023.106408},
author = {García-Lozano, María del Rosario and Rodríguez-Martínez, Alejandro and Rodríguez-Martínez},
}