2026-10-11T23:47:54Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33973529 2026-09-23T13:46:27Z category_1 category_4 category_7 category_12 category_13 category_19 category_21 category_272 category_873 category_39 category_734 category_64 category_132 portal_63 item_type_3 month_year_09_2026

Integrated Scaffold Redesign and iPSC-Based Screening Reveal Potent Antifibrotic Artemisinin Analogs in Systemic Sclerosis Models Takehiro Ishiga (25097666) Tetsuya Ikawa (25097669) Nobuto Kaneko (23180410) Norihito Takahashi (5489693) Krishanu Mondal (14294074) Yasuhiro Nakano (769181) Yutaro Hori (739774) Atsushi Miyajima (192348) Taketomo Kido (17120648) Yoshihide Asano (9748) Hiroki Oguri (1843054) Biophysics Biochemistry Medicine Cell Biology Genetics Pharmacology Biotechnology Environmental Sciences not elsewhere classified Chemical Sciences not elsewhere classified Ecology Biological Sciences not elsewhere classified Cancer Infectious Diseases unmet medical need systemic sclerosis patient providing mechanistic insight oriented molecular design intractable human disorders induced murine model observed therapeutic effects core cellular programs artemisinin scaffold led driven therapeutic discovery driven discovery platform combines scaffold redesign superior efficacy relative findings establish 6 integrated scaffold redesign level redesign observed even core fibrotic tissue remodeling therapies capable systematic modification relevant stem new chemotype natural products micromolar concentrations largely due inflammatory pathways fibrosis establishment enable next directly modulating derived fibroblasts based models antifibrotic intervention ameliorated fibrosis Fibrotic diseases remain among the most intractable human disorders, largely due to the absence of therapies capable of directly modulating the core cellular programs that drive pathological matrix deposition and tissue remodeling. To address this unmet medical need, we report an integrated, chemistry-driven discovery platform for function-oriented molecular design and discovery that combines scaffold redesign of a classical natural product pharmacophore with human induced pluripotent stem cell (iPSC)-based phenotypic screening to identify potent antifibrotic agents. Systematic modification of the artemisinin scaffold led to the identification of 6-aza-artemisinins with markedly enhanced antifibrotic activity, including an N6–N6′ dimeric analog exhibiting high potency at sub-micromolar concentrations. These compounds suppressed collagen production in systemic sclerosis patient-derived fibroblasts and ameliorated fibrosis in a bleomycin-induced murine model, with superior efficacy relative to the clinically used antimalarial drug artesunate. Notably, efficacy was observed even when treatment was initiated after fibrosis establishment. Transcriptomic analysis revealed coordinated suppression of core fibrotic and inflammatory pathways, providing mechanistic insight into the observed therapeutic effects. Collectively, these findings establish 6-aza-artemisinins as a new chemotype for antifibrotic intervention and illustrate how scaffold-level redesign of natural products, integrated with disease-relevant stem-cell-based models, can enable next-generation function-driven therapeutic discovery. 2026-09-23T00:00:00Z Dataset Dataset 10.1021/acscentsci.6c00658.s005 https://figshare.com/articles/dataset/Integrated_Scaffold_Redesign_and_iPSC-Based_Screening_Reveal_Potent_Antifibrotic_Artemisinin_Analogs_in_Systemic_Sclerosis_Models/33973529 CC BY-NC 4.0