2. Academic Validation
  3. 2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition

2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition

  • Sci Rep. 2021 Aug 30;11(1):17360. doi: 10.1038/s41598-021-96931-2.
Keiko Fukasawa # 1,  Mari Gotoh # 2,  Akiharu Uwamizu 3 4,  Takatsugu Hirokawa 5 6 7,  Masaki Ishikawa 8,  Yoshibumi Shimizu 1 9,  Shinji Yamamoto 10,  Kensuke Iwasa 10,  Keisuke Yoshikawa 10,  Junken Aoki 3 4,  Kimiko Murakami-Murofushi 11
Affiliations

Affiliations

  • 1 Ochadai Academic Production, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo, 112-8610, Japan.
  • 2 Institute for Human Life Innovation, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo, 112-8610, Japan. gotoh.mari@ocha.ac.jp.
  • 3 Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 4 AMED-LEAP and AMED-CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.
  • 5 Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
  • 6 Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
  • 7 Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
  • 8 Clinical Omics Unit, Department of Applied Genomics, Kazusa DNA Research Institute, 2-5-23 Kazusa Kamatari, Kisarazu, Chiba, 292-0818, Japan.
  • 9 Laboratory of Racing Chemistry, 1731-2 Tsurutamachi Utsunomiya, Tochigi, 320-0851, Japan.
  • 10 Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.
  • 11 Ochadai Academic Production, Ochanomizu University, 2-1-1 Ohtsuka, Bunkyo-ku, Tokyo, 112-8610, Japan. murofushi.kimiko@ocha.ac.jp.
  • # Contributed equally.
PMID: 34462512 DOI: 10.1038/s41598-021-96931-2
Abstract

Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA is similar to lysophosphatidic acid (LPA) in structure and synthetic pathway, some of cPA biological functions apparently differ from those reported for LPA. We previously investigated the pharmacokinetic profile of 2ccPA, which was found to be rapidly degraded, especially in acidic conditions, yielding an unidentified compound. Thus, not only cPA but also its degradation compound may contribute to the biological activity of cPA, at least for 2ccPA. In this study, we determined the structure and examined the biological activities of 2-carba-lysophosphatidic acid (2carbaLPA) as a 2ccPA degradation compound, which is a type of β-LPA analogue. Similar to LPA and cPA, 2carbaLPA induced the phosphorylation of the extracellular signal-regulated kinase and showed potent agonism for all known LPA receptors (LPA1-6) in the transforming growth factor-α (TGFα) shedding assay, in particular for LPA3 and LPA4. 2carbaLPA inhibited the lysophospholipase D activity of Autotaxin (ATX) in vitro similar to Other cPA analogues, such as 2ccPA, 3-carba-cPA, and 3-carba-LPA (α-LPA analogue). Our study shows that 2carbaLPA is a novel β-LPA analogue with high potential for the activation of some LPA receptors and ATX inhibition.

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