Abstract
Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6 + 4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer’s disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from a natural source and limited pharmacokinetic properties have hampered its further studies. Herein, we report the design, synthesis, and biological evaluation of 3-desoxycollinoketone B, a collinolactone derivative with improved pharmacokinetics for AD treatment. A stereoselective transannular [6 + 4] cycloaddition efficiently constructs the tricyclic core, allowing its scalable synthesis. AI-assisted binding prediction and simulations not only indicate superior binding of 3-desoxycollinoketone B to Aβ and tau aggregates to collinolactone, but also suggest a mechanistic basis for fibril destabilization. In vitro studies confirm its inhibition and dissociation of Aβ and tau fibrils, while in vivo experiments in AD mouse models show substantial amelioration of cognitive functions and Aβ/tau-associated pathology.
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Data availability
The data that support the findings of this study are available within the paper and its supplementary information files. Source data underlying the figures are provided with this paper. CCDC 2391862 contains the supplementary crystallographic data for compound 8a. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via [www.ccdc.cam.ac.uk/structures]. Source data are provided with this paper.
Code availability
The source codes for the models used in this study are publicly available at the following repositories: DiffDock-L [https://github.com/gcorso/DiffDock], NeuralPLexer2 [https://github.com/zrqiao/NeuralPLexer], and PIGNet2 [https://github.com/mseok/PIGNet2].
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Acknowledgements
We thank Dr. Dongwook Kim for analyzing the crystal structure of 8a, and Dr. Kyunghoon Lee for his assistance with the transition state calculations for the [6 + 4] cycloaddition. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2021R1A2C2011203, NRF-2018R1A5A1025208, NRF-2021R1A2C2093916, Y.K., RS-2023-00257479) and by the BK21 FOUR Project. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1A6A1A10073887). We acknowledge support by Korea Dementia Research Project through the Korea Dementia Research Center (KDRC) (RS-2024-00349158, Y.K.). This research was also supported by KAIST Cross-Generation Collaborative Lab Project.
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Seongrok H. synthesized and characterized chemicals. M.C. conducted the full series of pharmacological evaluations from in vitro to in vivo studies. W.Z. performed the molecular simulation analyses. Seongrok H., M.C., Y.K., and Sunkyu H. wrote the original draft. J.K. participated in 5XFAD long-term drug administration. S.K. assisted in large-scale compound synthesis. J.K. and H.S. were involved in mouse breeding. I.C. and M.P. synthesized fluorescent Aβ peptides. Soljee Y. and W.S. synthesized the R3 peptide. W.S. and Suhyun Y. synthesized Aβ42 peptide. J.H. and H.H. carried out the ADME analyses. Seongrok H., M.C., W.Z., W.Y.K., Y.K., and Sunkyu H. analyzed and interpreted the data and wrote the paper. W.Y.K., Y.K., and Sunkyu H. supervised the entire work.
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Y.K. is an employee of Amyloid Solution Inc. and received equity or equity options. The remaining authors declare no competing interests.
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Heo, S., Cha, M., Zhung, W. et al. Synthesis of 3-desoxycollinoketone B and its ability to reduce Alzheimer-associated misfolded proteins. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69662-z
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DOI: https://doi.org/10.1038/s41467-026-69662-z
