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
  • 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: [email protected].
  • 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: [email protected].
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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