Expedited access to polyunsaturated fatty acids and biofunctional analogues by full solid-phase synthesis | Nature Chemistry

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Polyunsaturated fatty acids (PUFAs) represent a fundamental and essential class of lipids that exhibit versatile biofunctions. Lipidomic analysis has identified a growing number of lipid species, including PUFAs with diverse structural variations and biofunctions, yet their structure–function relationships are still largely unknown. In this context, an efficient synthesis of PUFAs would be highly desirable. However, no practical methodology exists for their preparation, in contrast to peptides and nucleic acids, for which diverse molecules are accessible through a well-established solid-phase synthesis. To address this, we have developed an efficient and expedited method to access a wide array of PUFAs by full solid-phase synthesis. The method allows the synthesis of various PUFAs and analogues through rapid and facile operations. Moreover, within our PUFA library, we have discovered an artificial fatty acid, antiefin, that has a high anti-inflammatory effect in vivo. Therefore, our practical synthetic pathway to PUFAs, a crucial class of lipids, is expected to make an important contribution to lipid science.

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This work was performed in part at the One-stop Sharing Facility Center for Future Drug Discoveries in the Graduate School of Pharmaceutical Sciences, The University of Tokyo. We thank K. Nozaki, T. Iwasaki and X. Jin (The University of Tokyo) for fruitful discussions and support with GC measurements. The atomic absorption measurements were performed at the Common Facilities of the Analytical Chemistry Laboratory, Department of Applied Chemistry, School of Engineering, The University of Tokyo. We thank T. Yamagishi (The University of Tokyo) for fruitful discussions and support with the atomic absorption measurements. This research was supported by JSPS KAKENHI (grant nos. JP22K14780 (to Y. Saito) and JP22KJ1101 (to M.A.)), AMED (grant no. JP233fa727001 (to Y. Saito and J.K.)), the Toyota Riken Scholar Program (to Y. Saito), the Mizuho Foundation for the Promotion of Sciences (to Y. Saito), KONICA MINOLTA Award in Synthetic Organic Chemistry, Japan (to Y. Saito) and JST-CREST (grant no. JPMJCR21N5 (to S.S.)).

Azusa Saika

Present address: Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore, Singapore

Takahiro Nagatake

Present address: Laboratory of Functional Anatomy, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan

These authors contributed equally: Yutaro Saito, Mayuko Akita, Azusa Saika.

Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

Yutaro Saito, Mayuko Akita, Yusuke Sano, Jumpei Morimoto & Shinsuke Sando

Laboratory of Vaccine Materials, Laboratory of Gut Environmental System, Microbial Research Center for Health and Medicine, National Institutes of Biomedical Innovation, Health and Nutrition (NIBN), Osaka, Japan

Azusa Saika, Masashi Hotta, Takahiro Nagatake & Jun Kunisawa

Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Akiharu Uwamizu & Junken Aoki

Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Hyogo, Japan

Jun Kunisawa

International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Jun Kunisawa

Graduate School of Medicine, Graduate School of Dentistry, Graduate School of Pharmaceutical Sciences, Department of Science, The University of Osaka, Osaka, Japan

Jun Kunisawa

Research Organization for Nano and Life Innovation, Waseda University, Tokyo, Japan

Jun Kunisawa

Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

Shinsuke Sando

Search author on:PubMed Google Scholar

Y. Saito, J.K. and S.S. conceived and designed the project. Y. Saito, M.A. and Y. Sano performed the synthetic experiments with the help of J.M. and S.S. Y. Saito, M.A., A.S., M.H. and T.N. performed the cellular experiments with the help of A.U., J.A., J.K. and S.S. A.S., M.H. and T.N. performed the animal experiments with the help of J.K. Finally, Y. Saito, M.A. and S.S wrote the paper, which was edited by all of the co-authors.

Correspondence to Yutaro Saito, Jun Kunisawa or Shinsuke Sando.

Y. Saito, M.A., Y. Sano and S.S. have filed a patent application related to the preparation method of polyunsaturated fatty acids on a solid phase (patent applicant: The University of Tokyo; inventors: Y. Saito, S.S., M.A., Y. Sano and Yaohong Shi; international Patent application number: PCT/JP2025/011856; current application status: pending). All other authors declare no competing interests.

Nature Chemistry thanks Anna Sansone and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Materials and Methods, Figs. 1–4, Tables 1–6, NMR spectra and HPLC, LC–MS and GC chromatograms.

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Saito, Y., Akita, M., Saika, A. et al. Expedited access to polyunsaturated fatty acids and biofunctional analogues by full solid-phase synthesis. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01853-5

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Received: 08 July 2024

Accepted: 14 May 2025

Published: 25 June 2025

DOI: https://doi.org/10.1038/s41557-025-01853-5

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