Identification of Benzothiophene-derived Inhibitors of Flaviviruses by Targeting RNA-dependent RNA Polymerase

Authors

• Leah Liu Wang, University of Nebraska-Lincoln
• Shazeed-Ul Karim, University of Southern Mississippi
• Aidan Hand, University of Nebraska-Lincoln
• Ryan Brunkhorst, University of Nebraska-Lincoln
• Mackenna Petersen, University of Nebraska-Lincoln
• Sarah Altam, University of Nebraska-Lincoln
• Yi Liu, University of Nebraska-LincolnFollow
• Luwen Zhang, University of Nebraska-LincolnFollow
• Fengwei Bai, University of Southern MississippiFollow
• Shi-Hua Xiang, University of Nebraska-LincolnFollow

ORCID IDs

Liu https://orcid.org/0000-0002-0879-0487

Xiang https://orcid.org/0000-0002-5656-5698

Document Type

Article

Date of this Version

2025

Citation

Viruses (2025) 17: 145

doi: 10.3390/v17020145

Comments

Open access

License: CC BY 4.0

Abstract

Flaviviruses such as Dengue, West Nile, and Zika viruses are mosquito-borne RNA viruses that can cause serious diseases in humans. To develop effective drugs for treating these viruses’ infections, we create a new approach for developing common or shared drugs that may work for several different viral species of flaviviruses. It is based on the conserved RNA-dependent RNA polymerase (RdRp), which is the key enzyme for viral replication. We built up a common structure of RdRps (POLcon) from their consensus sequence. A conserved Triple-D structural motif was identified at the active site of POLcon that has been used for virtual compound screening. We have identified three inhibitors that have potent activities against Dengue, West Nile, and Zika viruses. All these three inhibitors are Benzothiophene derivatives. This is the first report of Benzothiophene-derived compounds as inhibitors for flaviviruses. Furthermore, our approach has provided a proof-of-concept that it is feasible to identify shared drugs for several different viral species of flaviviruses.