posted on 2019-07-19, 12:06authored byJi Yoon Beom, Jin A Jung, Kyung-Tae Lee, Areum Hwangbo, Myoung Chong Song, Yeonseon Lee, Soo Jung Lee, Ji Hoon Oh, Sang-Jun Ha, Sang-Jip Nam, Eunji Cheong, Yong-Sun Bahn, Yeo Joon Yoon
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–FK506–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.