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(The FASEB Journal. 2008;22:lb619)
© 2008 FASEB
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lb619

Binding of novel rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

Benfang Helen Ruan1, Kevin Pong3, Flora Jow3, Mark Bowlby3, Robert Crozier3, Danni Liu3, Shi Liang3, Yi Chen3, Mary Lynn Mercado3, Xiaodong Feng4, Frann Bennett1, David von Schack2, Leonard McDonald4, Margaret Zaleska3, Andrew Wood3, Peter Reinhart3, Ronald L. Magolda4, Jerauld Skotnicki4, Menelas N. Pangalos3, Frank E. Koehn4, Guy Carter4, Magid Abou-Gharbia4 and Edmund Graziami4

1 Inflammation,
2 Biological Technologies, Wyeth, Cambridge, MA,
3 Neuroscience, Wyeth, Princeton, NJ,
4 Chemical and Screening Science, Wyeth, Pearl River, NY

ABSTRACT

Rapamycin is an immunosuppressive immunophilin ligand reported as having in vitro neuroprotective activity. WYE-592 and ILS-920, synthesized by modifying rapamycin at the mTOR binding region, showed reduced immunosuppressive activity and enhanced neuroprotective activities. Also, ILS-920 demonstrated efficacy in an in vivo stroke model. This stimulated our interest in identifying potential targets that may be important in post-ischemic recovery. Affinity precipitation from a dorsal root ganglia/neuroblastoma (F11) cell lysate revealed that ILS-920 predominantly binds to FKBP52 and the β-subunit of L-type voltage dependent Ca2+channels. Further, kinetic analysis demonstrated that ILS-920 had a 972-fold higher selectivity for FKBP52 vs. FKBP12 than that of rapamycin. The involvement of FKBP52 and the β-subunit in the mechanism of neurite outgrowth was established by gene deletions. Electrophysiological analysis showed that IL-920 reduced 49% of total Ca2+ current, and inhibited the L-type Ca2+channels in rat hippocampal neurons, in contrast to rapamycin. These data suggest that this dual functionality- FKBP52 binding that stimulates neurite outgrowth perhaps via modulation of glucocorticoid and other steroid receptors, and inhibition of Ca2+ channel function to prevent neuronal cell death- may contribute to the compound’s efficacy in stroke models.





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