Biosynthesis of Nonimmunosuppressive ProlylFK506 Analogues with Neurite Outgrowth and Synaptogenic Activity

Jin A. Jung, Heon Joo Lee, Myoung Chong Song, Areum Hwangbo, Ji Yoon Beom, Soo Jung Lee, Dong Jin Park, Ji Hoon Oh, Sang Jun Ha, Eunji Cheong, Yeo Joon Yoon

Research output: Contribution to journalArticlepeer-review

Abstract

Separating the immunosuppressive activity of FK506 (1) from its neurotrophic activity is required to develop FK506 analogues as drugs for the treatment of neuronal diseases. Two new FK506 analogues, 9-deoxo-36,37-dihydro-prolylFK506 (2) and 9-deoxo-31-O-demethyl-36,37-dihydro-prolylFK506 (3) containing a proline moiety instead of the pipecolate ring at C-1 and modifications at the C-9/C-31 and C-36-C-37 positions, respectively, were biosynthesized, and their biological activities were evaluated. The proline substitution in 9-deoxo-36,37-dihydroFK506 and 9-deoxo-31-O-demethyl-36,37-dihydroFK506 reduced immunosuppressive activity by more than 120-fold, as previously observed. Compared with FK506 (1), 2 and 3 exhibited ∼1.2 × 105- and 2.2 × 105-fold reductions in immunosuppressive activity, respectively, whereas they retained almost identical neurite outgrowth activity. Furthermore, these compounds significantly increased the strength of synaptic transmission, confirming that replacement of the pipecolate ring with a proline is critical to reduce the strong immunosuppressive activity of FK506 (1) while enhancing its neurotrophic activity.

Original languageEnglish
JournalJournal of Natural Products
DOIs
Publication statusAccepted/In press - 2021

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT (MSIT) (2019R1A2B5B03069338; ; 2017M3C7A1023471, 2020R1A4A1019009), Bio & Medical Technology Development Program of the NRF funded by the MSIT (2018M3A9F3079662), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (HI18C1664, HU20C0066), and the New Faculty Startup Fund from Seoul National University.

Publisher Copyright:
© 2021 American Chemical Society and American Society of Pharmacognosy.

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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