Development of synthesis method for polyunsaturated fatty acids — Expectations for the development of novel anti-inflammatory fatty acid

Polyunsaturated fatty acids such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) are important biomolecules that perform various functions in living organisms. With advances in analytical technology, it has become clear that a wide variety of polyunsaturated fatty acids exist in living organisms, and their relationship with life functions and diseases has attracted attention. To clarify the properties and functions of each polyunsaturated fatty acid, it is necessary to obtain the target polyunsaturated fatty acids and structurally similar molecules through chemical synthesis for investigation. However, conventional chemical synthesis required advanced techniques and significant effort and time, so development of methods that could efficiently and precisely synthesize polyunsaturated fatty acids was desired.

A research group led by Research Associate Yutaro Saito, Graduate Student Mayuko Akita (at the time of the research), and Professor Shinsuke Sando from the Graduate School of Engineering at the University of Tokyo, in collaboration with Professor Junken Aoki from the Graduate School of Pharmaceutical Sciences at the same university and Deputy Director Jun Kunisawa from the Microbial Research Center for Health and Medicine at the National Institutes of Biomedical Innovation, Health and Nutrition, developed a full solid-phase synthesis method for polyunsaturated fatty acids and discovered a new anti-inflammatory fatty acid using the developed technology. The findings were published in Nature Chemistry.

This research was inspired by solid-phase synthesis, a versatile chemical synthesis method for biomolecules such as peptides and nucleic acids and developed the world's first full solid-phase synthesis method for polyunsaturated fatty acids. Unlike liquid-phase synthesis, which is a common organic synthesis method, solid-phase synthesis is a technique that excels in parallel synthesis, enabling rapid and simple reaction and purification operations and the simultaneous synthesis of diverse molecules. Originally developed as a synthesis method for peptides, it was later applied to the synthesis of nucleic acids and glycans, and its usefulness earned the Nobel Prize in Chemistry in 1984. In the present, it has been developed for automated synthesis of peptides and nucleic acids and is widely used in practice at both laboratory and industrial levels. However, solid-phase synthesis excels with macromolecules (oligomers or polymers) where common molecular structures (monomers) are regularly connected, such as peptides and nucleic acids. Synthesis by full solid-phase synthesis had not been achieved for polyunsaturated fatty acids, which do not have this molecular form.

While conventional synthesis methods required several weeks to months to synthesize one type of polyunsaturated fatty acid, the newly developed method makes it possible to synthesize multiple types of polyunsaturated fatty acids simultaneously in a few hours to days.

The research team used the synthesis method they developed to artificially synthesize 18 types of polyunsaturated fatty acids, including completely new ones, and discovered a new fatty acid with anti-inflammatory effects called antiefin. In previous research, Kunisawa's group had found that 17,18-EpETE, which is produced in the body from α-linolenic acid (the main component of linseed oil) via EPA, showed anti-inflammatory effects. However, 17,18-EpETE is easily metabolized in the body and loses its anti-inflammatory effects, which was a challenge for practical implementation. The newly discovered fatty acid antiefin showed anti-inflammatory effects at lower concentrations than 17,18-EpETE in cell experiments, and in animal experiments using contact dermatitis model mice, inflammation was suppressed by applying just 10 nanograms to the skin twice.

The solid-phase synthesis method developed in this research can synthesize diverse polyunsaturated fatty acids simply and efficiently and is expected to be applied to automation and data-driven life science research using large-scale data. Following on from peptide drug discovery and nucleic acid drug discovery, which are currently flourishing in the drug discovery field, it has the potential to contribute to the development of lipid science research and create societal impact that promotes the development of lipid drug discovery.

Journal Information
Publication: Nature Chemistry
Title: Expedited access to polyunsaturated fatty acids and biofunctional analogues by full solid-phase synthesis
DOI: 10.1038/s41557-025-01853-5