Identification of Benzothiophene-Derived Inhibitors of Flaviviruses by Targeting RNA-Dependent RNA Polymerase
Leah Liu Wang,
Shazeed-Ul Karim,
Aidan Hand,
Ryan Brunkhorst,
Mackenna Petersen,
Sarah Altman,
Yi Liu,
Luwen Zhang,
Fengwei Bai,
Shi-Hua Xiang
Affiliations
Leah Liu Wang
Nebraska Center for Virology and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
Shazeed-Ul Karim
Department of Cell and Molecular Biology, School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi, Hattiesburg, MS 39406, USA
Aidan Hand
Nebraska Center for Virology and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
Ryan Brunkhorst
Nebraska Center for Virology and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
Mackenna Petersen
Nebraska Center for Virology and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
Sarah Altman
Nebraska Center for Virology and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
Yi Liu
Holland Computing Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
Luwen Zhang
School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
Fengwei Bai
Department of Cell and Molecular Biology, School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi, Hattiesburg, MS 39406, USA
Shi-Hua Xiang
Nebraska Center for Virology and School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
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.
