7-O-sulfonation redirects luteolin’s target preference from furin to NS2B/NS3 and enhances anti-dengue activity
- 1Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou , ,
- 2Chinese Medicine Guangdong Laboratory, Hengqin , ,
- 3School of Medicine, The Sixth Affiliated Hospital of South China University of Technology (Nanhai District People’s Hospital of Foshan), Foshan , ,
Abstract
Background: Dengue virus (DENV) infection remains a global health threat with no approved small-molecule antiviral for clinical use. Luteolin, a natural flavonoid, exhibits anti-dengue activity but suffers from poor solubility and moderate potency. The 7-O position is the primary site of metabolic glucuronidation, whereas the 5-O position is sequestered by intramolecular hydrogen bonding, offering structurally distinct positions for derivatization.
Methods: Five site-selective derivatives of luteolin (three 5-O- and two 7-O-substituted) were synthesized. Their anti-DENV activity was evaluated in Vero cells by qRT-PCR (measuring viral RNA abundance) and plaque assays, and cytotoxicity was determined using the CCK8 method. For mechanistic exploration, enzymatic inhibition kinetics against NS2B/NS3 and furin were measured, and target engagement was further assessed via molecular docking and cellular thermal shift assays (CETSA).
Results: Among the derivatives, compound 5, bearing a 4-fluorobenzenesulfonyl group at the 7-O position, exhibited the most potent anti-DENV activity (EC ₅₀ = 0.46 μM) and the highest selectivity index (SI = 28.5), representing an 18-fold increase in antiviral potency over luteolin. In enzymatic assays, compound 5 showed preferential inhibition of the viral NS2B/NS3 protease ( K i = 11.54 μM) over the host furin ( K i = 93 μM). Molecular docking and thermal stabilization assays provided correlative evidence supporting target engagement with both proteases.
Conclusion: Site-selective 7-O-sulfonation of luteolin yields compound 5, a derivative with improved anti-DENV activity and selectivity that shows preferential NS2B/NS3 inhibition in enzymatic assays. This study provides a structural framework for the further optimization of flavonoid-based antiviral agents.
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BibTeX
@article{chen20267osulfonation,
title = {{7-O-sulfonation redirects luteolin’s target preference from furin to NS2B/NS3 and enhances anti-dengue activity}},
author = {Huini Chen and Zizhao Lao and Yuhang Huo and Liangwen Yu and Wen Zhou and Geng Li},
journal = {Frontiers in microbiology},
year = {2026},
month = oct,
doi = {10.3389/fmicb.2026.1931544},
url = {https://europepmc.org/article/PMC/PMC13672209},
note = {CC BY},
}
RIS
TY - JOUR
TI - 7-O-sulfonation redirects luteolin’s target preference from furin to NS2B/NS3 and enhances anti-dengue activity
AU - Huini Chen
AU - Zizhao Lao
AU - Yuhang Huo
AU - Liangwen Yu
AU - Wen Zhou
AU - Geng Li
PY - 2026
DA - 2026/10/02
JO - Frontiers in microbiology
DO - 10.3389/fmicb.2026.1931544
UR - https://europepmc.org/article/PMC/PMC13672209
AB - Background: Dengue virus (DENV) infection remains a global health threat with no approved small-molecule antiviral for clinical use. Luteolin, a natural flavonoid, exhibits anti-dengue activity but suffers from poor solubility and moderate potency. The 7-O position is the primary site of metabolic glucuronidation, whereas the 5-O position is sequestered by intramolecular hydrogen bonding, offering structurally distinct positions for derivatization. Methods: Five site-selective derivatives of luteolin (three 5-O- and two 7-O-substituted) were synthesized. Their anti-DENV activity was evaluated in Vero cells by qRT-PCR (measuring viral RNA abundance) and plaque assays, and cytotoxicity was determined using the CCK8 method. For mechanistic exploration, enzymatic inhibition kinetics against NS2B/NS3 and furin were measured, and target engagement was further assessed via molecular docking and cellular thermal shift assays (CETSA). Results: Among the derivatives, compound 5, bearing a 4-fluorobenzenesulfonyl group at the 7-O position, exhibited the most potent anti-DENV activity (EC ₅₀ = 0.46 μM) and the highest selectivity index (SI = 28.5), representing an 18-fold increase in antiviral potency over luteolin. In enzymatic assays, compound 5 showed preferential inhibition of the viral NS2B/NS3 protease ( K i = 11.54 μM) over the host furin ( K i = 93 μM). Molecular docking and thermal stabilization assays provided correlative evidence supporting target engagement with both proteases. Conclusion: Site-selective 7-O-sulfonation of luteolin yields compound 5, a derivative with improved anti-DENV activity and selectivity that shows preferential NS2B/NS3 inhibition in enzymatic assays. This study provides a structural framework for the further optimization of flavonoid-based antiviral agents.
SN - 1664-302X
ER -