The Antiviral Activity of Varenicline against Dengue Virus Replication during the Post-Entry Stage

Ching-Lin Lin; Yan-Tung Kiu; Ju-Ying Kan; Yu-Jen Chang; Ping-Yi Hung; Chih-Hao Lu; Wen-Ling Lin; Yow-Wen Hsieh; Jung-Yie Kao; Nien-Jen Hu; Cheng-Wen Lin

doi:10.3390/biomedicines11102754

The Antiviral Activity of Varenicline against Dengue Virus Replication during the Post-Entry Stage

Biomedicines. 2023 Oct 11;11(10):2754. doi: 10.3390/biomedicines11102754.

Authors

Ching-Lin Lin¹, Yan-Tung Kiu², Ju-Ying Kan^{2

3}, Yu-Jen Chang³, Ping-Yi Hung², Chih-Hao Lu⁴, Wen-Ling Lin^{5

6}, Yow-Wen Hsieh^{5

6}, Jung-Yie Kao¹, Nien-Jen Hu¹, Cheng-Wen Lin^{2

3

7}

Affiliations

¹ Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
² Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404328, Taiwan.
³ The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung 404328, Taiwan.
⁴ Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu City 30010, Taiwan.
⁵ Department of Pharmacy, China Medical University Hospital, Taichung 404328, Taiwan.
⁶ School of Pharmacy, China Medical University, Taichung 404328, Taiwan.
⁷ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan.

Abstract

Dengue virus (DENV) poses a significant global health challenge, with millions of cases each year. Developing effective antiviral drugs against DENV remains a major hurdle. Varenicline is a medication used to aid smoking cessation, with anti-inflammatory and antioxidant effects. In this study, varenicline was investigated for its antiviral potential against DENV. This study provides evidence of the antiviral activity of varenicline against DENV, regardless of the virus serotype or cell type used. Varenicline demonstrated dose-dependent effects in reducing viral protein expression, infectivity, and virus yield in Vero and A549 cells infected with DENV-1 and DENV-2, with EC50 values ranging from 0.44 to 1.66 μM. Time-of-addition and removal experiments demonstrated that varenicline had a stronger inhibitory effect on the post-entry stage of DENV-2 replication than on the entry stage, as well as the preinfection and virus attachment stages. Furthermore, cell-based trans-cleavage assays indicated that varenicline dose-dependently inhibited the proteolytic activity of DENV-2 NS2B-NS3 protease. Docking models revealed the formation of hydrogen bonds and van der Waals forces between varenicline and specific residues in the DENV-1 and DENV-2 NS2B-NS3 proteases. These results highlight the antiviral activity and potential mechanism of varenicline against DENV, offering valuable insights for further research and development in the treatment of DENV infection.

Keywords: NS2B-NS3 protease; antiviral; cleavage assay; dengue virus; post entry; varenicline.

Grants and funding

This study was supported by Taiwan’s National Science and Technology Council (MOST110-2923-B-039-001-MY3 and MOST111-2923-B-039-001-MY3), China Medical University (CMU111-S-18 and CMU111-MF-96), and China Medical University Hospital (DMR-112-149). The study was also supported by the Drug Development Center, China Medical University, from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education, Taiwan (CMU-DDCCENTER-TD3-2).