2. Academic Validation
  3. Darunavir inhibits dengue virus replication by targeting the hydrophobic pocket of the envelope protein

Darunavir inhibits dengue virus replication by targeting the hydrophobic pocket of the envelope protein

  • Biochem Pharmacol. 2025 May:235:116839. doi: 10.1016/j.bcp.2025.116839.
Ju-Ying Kan 1,  Yu-Jen Chang 2,  Hsueh-Chou Lai 3,  Hsiao-Hsuan Lin 4,  Shih-Wen Chiu 5,  Ping-Yi Hung 4,  Chih-Hao Lu 6,  Cheng-Wen Lin 7
Affiliations

Affiliations

  • 1 The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
  • 2 The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan.
  • 3 Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung 404332, Taiwan.
  • 4 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
  • 5 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan.
  • 6 Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan. Electronic address: chlu@nycu.edu.tw.
  • 7 The Ph.D. Program of Biotechnology and Biomedical Industry, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan. Electronic address: cwlin@mail.cmu.edu.tw.
PMID: 40024350 DOI: 10.1016/j.bcp.2025.116839
Abstract

Dengue viruses (DENV) pose significant health threats, with no approved Antiviral drugs currently available, creating an urgent need for new therapies. This study screened FDA-approved drugs for their Antiviral ability against DENV and identified three promising candidates: darunavir (DRV), domperidone, and Tetracycline. DRV demonstrated the highest efficacy against three DENV serotypes, with half-maximal effective concentrations (EC50) below 1 µM, surpassing the performance of Tetracycline and domperidone. It effectively blocked DENV envelope (E) protein attachment to two type cells with EC50 values less than 0.2 μM. Domperidone reduced DENV-2 attachment to TE671 cells (EC50 = 3.08 μM) but was less effective in BHK-21 cells, while Tetracycline inhibited NS3 protease (IC50 = 1.12 μM). Among DRV's structurally related drugs, fosamprenavir (FPV) significantly reduced DENV infectivity and virus yield, with EC50 values below 0.5 µM. In vivo, DRV at 1, 2, and 5 mg/kg achieved 100 % survival in suckling mice, compared to 83.5 % with FPV. Real-time RT-PCR showed DRV more effectively reduced DENV-2 RNA in mouse brains than FPV. Molecular docking showed DRV and FPV bind tightly to the DENV-2 E protein's N-octyl-β-D-glucoside (βOG) hydrophobic pocket, with DRV forming stronger interactions than FPV. Chimeric DENV-2 single-round infectious particle tests confirmed DRV's effective targeting of this pocket, though mutations at K128, L198, Q200, I270, and T280 reduced its efficacy. These findings highlight DRV as a potent Antiviral agent against DENV, targeting the E protein's βOG hydrophobic pocket, with the potential for rapid deployment in treating and preventing infections.

Keywords

Darunavir; Dengue virus; Drug repurposing; Envelope protein; Fosamprenavir; N-octyl-β-D-glucoside pocket.

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