Giulia Atzeni
| Identification of dual NS3 protease-helicase inhibitors as broad-spectrum antivirals against WNV and ZIKV |
| Atzeni Giulia1,2, Lupia Antonio1, Emmolo Roberta1, Corona Angela1, Nieddu Salvatore1, Esposito Francesca1, Sanna Erica1, Onali Alessia1, Demuru Laura1, Meleddu Rita1, Cottiglia Filippo1, Tramontano Enzo1 and Maccioni Elias1 1 Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy 2 National PhD Programme in One Health approaches to infectious diseases and life science research, Department of Public Health, University of Pavia |
| Abstract Nowadays, zoonosis caused by Flaviviruses such as West Nile or Dengue virus represent a global health concern because they cause serious diseases such as encephalitis or haemorrhagic fever. To date, no antiviral treatments are available [1]. The 11-kb positive-sense, single-stranded RNA (ssRNA) genome is translated into a single polyprotein, which is subsequently cleaved into three structural proteins (C, prM/M, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Among them, NS3 is a multifunctional, highly conserved flavivirus protein that integrates protease and helicase functions and is indispensable for viral maturation, replication, and infectivity [2]. While most antiviral efforts focus on single-target inhibitors, dual inhibitors targeting both protease and helicase activities offer the potential for enhanced efficacy and reduced resistance. Using Computer-Aided Drug Design (CADD), we identified a series of compounds capable of inhibiting both NS3 helicase and protease activities of West Nile virus (WNV) and Zika virus (ZIKV) at low micromolar concentrations. Scaffold optimization through multiple structural modifications is ongoing to improve antiviral potency and reduce cytotoxicity. Pure enantiomers of the most active compound were isolated and evaluated, showing no significant difference in biological activity. These findings underscore the promise of broad-spectrum dual NS3 inhibitors as an effective antiviral strategy against flaviviruses. |
| References [1] S. Madere, et all. Flavivirus infections and diagnostic challenges for dengue, West Nile and Zika Viruses. Viruses, 2025 [2] R. Assenberg, et all. Crystal Structure of a Novel Conformational State of the Flavivirus NS3 Protein: Implications for Polyprotein Processing and Viral Replication. J. Virol.2009 Sep 30 Acknowledgments This research was supported by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT) |