Vu, Ngoc Khanh Choi, Ji-Wan Hwang, Hoseong Lee, Hyeon-Seong Cho, Su-Yeon Park, Keunwan Kwon, Hak Cheol Kim, Won Kyu Song, Yoon-Jae Kwon, Jaeyoung 2026-02-19T06:00:04Z 2026-02-19T06:00:04Z 2026-02-19 2026-04 0045-2068 https://pubs.kist.re.kr/handle/201004/154306 Although highly effective direct-acting antivirals are available, hepatitis C virus (HCV) infection remains a major global health challenge, causing approximately 200,000 deaths annually, thereby highlighting the need for alternative therapeutic strategies. In this study, extracts of Iris odaesanensis, a plant endemic to Korea, suppressed HCV replication, with the butanol fraction exhibiting particularly potent activity. Molecular networking analysis identified xanthones as the major constituents responsible for this effect. Bioactivity-guided isolation led to the characterization of 11 xanthones, including four new compounds, along with three metabolites from other structural classes. Their structures were elucidated through comprehensive spectroscopic analyses. Among them, compounds 7–9 and 14 demonstrated notable anti-HCV activity. Compounds 7 and 8 inhibited viral polyprotein synthesis mediated by the internal ribosome entry site sequence during the post-entry stages of the HCV life cycle. In addition, evolutionary chemical binding similarity model–based target prediction suggested potential protein targets for these compounds. Compounds 9 and 14 inhibited HCV NS3/4A protease activity in enzymatic assays, while molecular docking provided supportive evidence for binding. All four active compounds suppressed NS5B RNA-dependent RNA polymerase activity in vitro, and docking studies suggested stable interactions within the enzyme's active site. Collectively, these findings highlight I. odaesanensis and its components as potential natural resources for developing multitarget anti-HCV agents, with both experimental validation and in silico predictions contributing to the mechanistic understanding. English Academic Press Antiviral constituents of the Korean endemic plant Iris odaesanensis inhibit hepatitis C virus through multiple targets Article 10.1016/j.bioorg.2026.109555 1 Bioorganic Chemistry, v.171 Bioorganic Chemistry 171 N scie scopus 001682374300001 2-s2.0-105029025249 Biochemistry & Molecular Biology Chemistry, Organic Biochemistry & Molecular Biology Chemistry Article INFECTION EXPRESSION GLYCOSIDES MECHANISM PROTEINS XANTHONE THERAPY HEME SITE NS3 Xanthones Hepatitis C virus NS3/4A NS5B Iris odaesanensis