2026-10-13T22:12:37Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34053843 2026-10-02T04:40:12Z category_8 portal_316 item_type_3 month_year_10_2026

Table 1_7-O-sulfonation redirects luteolin’s target preference from furin to NS2B/NS3 and enhances anti-dengue activity.docx Huini Chen (7865960) Zizhao Lao (7865969) Yuhang Huo (10678989) Liangwen Yu (10269809) Wen Zhou (49050) Geng Li (312002) Microbiology antiviral dengue virus luteolin derivatives molecular docking NS2B/NS3 protease Background<p>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.</p>Methods<p>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).</p>Results<p>Among the derivatives, compound 5, bearing a 4-fluorobenzenesulfonyl group at the 7-O position, exhibited the most potent anti-DENV activity (EC₅₀ = 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.</p>Conclusion<p>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.</p> 2026-10-02T04:40:12Z Dataset Dataset 10.3389/fmicb.2026.1931544.s001 https://figshare.com/articles/dataset/Table_1_7-O-sulfonation_redirects_luteolin_s_target_preference_from_furin_to_NS2B_NS3_and_enhances_anti-dengue_activity_docx/34053843 CC BY 4.0