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Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity

Title
Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity
Authors
Beom, Ji YoonJung, Jin A.Lee, Kyung-TaeHwangbo, AreumSong, Myoung ChongLee, YeonseonLee, Soo JungOh, Ji HoonHa, Sang-JunNam, Sang-JipCheong, EunjiBahn, Yong-SunYoon, Yeo Joon
Ewha Authors
윤여준송명종남상집
SCOPUS Author ID
윤여준scopus; 송명종scopus; 남상집scopus
Issue Date
2019
Journal Title
JOURNAL OF NATURAL PRODUCTS
ISSN
0163-3864JCR Link

1520-6025JCR Link
Citation
JOURNAL OF NATURAL PRODUCTS vol. 82, no. 8, pp. 2078 - 2086
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS
Document Type
Article
Abstract
A reduction in the strong immunosuppressive activity of FK506 (1) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (7) exhibited a >900-fold reduction in the in vitro immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. 7 exhibited robust synergistic antifungal activity with fluconazole. FK506 (1) is a 23-membered macrolide produced by several Streptomyces species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca2+-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FIC506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.
DOI
10.1021/acs.jnatprod.9b00144
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자연과학대학 > 화학·나노과학전공 > Journal papers
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