Non-FK506-binding protein-12 neuroimmunophilin ligands increase neurite elongation and accelerate nerve regeneration

Abstract

Neurotrophic activity of neuroimmunophilin ligands (FK506 and its nonimmunosuppressant derivatives) has been assumed to be mediated by the FK506-binding protein-12 (FKBP-12). We recently showed that activity is retained in hippocampal neurons from FKBP-12 knockout mice, indicating that binding to FKBP-12 is not necessary. Here we show that three nonimmunosuppressant FK506 derivatives (V-13,450, V-13,629, and V-13,670) that do not bind FKBP-12 (>12.5 mM affinity) are equipotent to FKBP-12 ligands (FK506, V-10,367, and V-13,449) for increasing neurite elongation in SH-SY5Y cells. One non-FKBP-12 ligand (V-13,670) is also shown to accelerate functional recovery and nerve regeneration in the rat sciatic nerve crush model. Surprisingly, it exhibited an unusual dose-response effect upon oral administration, showing a novel bimodal dose-response for behavioral functional recovery and myelination, but not for axonal size, suggesting both Schwann cell and neuronal targets. Orally active non-FKBP-12 neuroimmunophilin ligands may be useful for the treatment of human neurological disorders without any potential side effects resulting from FKBP-12 binding.

Organization of the biosynthetic gene cluster in Streptomyces sp. DSM 4137 for the novel neuroprotectant polyketide meridamycin

“…Both studies indicate that binding to FKBP-12 is not required for neurotrophic activity. Similarly, non-immunosuppressant derivatives of FK506 that lack FKBP-12 binding are found to stimulate neurite elongation in SH-SY5Y cells (Gold et al, 2005). It is likely that binding to members of the FKBP family other than FKBP-12 underlies the neurotrophic activity of these agents.…”

Nocardiopsins: New FKBP12‐Binding Macrolide Polyketides from an Australian Marine‐Derived Actinomycete, Nocardiopsis sp.

“…[7] The only other known natural product members of this structure class are meridamycin, from a Venezuelan isolate of Streptomyces hygroscopius, [8] and the antascomicins, from a Chinese soil Micromonospora sp., [9] which also bind to FKBP12 but are not immunosuppressive. Recent literature reports note that FKBP-binding polyketides can exhibit separate and distinct immunosuppressive and neurotrophic pharmacologies, [10] with non-immunosuppressive inhibitors of FKBPs having potential application against important neurological disorders such as multiple sclerosis, [11] traumatic spinal cord injury [12] and Parkinsons disease. [13] In the absence of new natural product members of this structure class, exploration of the pharmacophore defined by FK506 and rapamycin has relied on virtual screening, [14] genetic engineering [15] and precursor-directed biosynthesis, the latter manipulating polyketide synthases (PKS) to incorporate unnatural starter unit carboxylic acids, [16] chain units [17] and terminating pipecolic acid mimics.…”

3-Normeridamycin: A Potent Non-Immunosuppressive Immunophilin Ligand is Neuroprotective in Dopaminergic Neurons

“…Subsequent studies, spanning the last decade, revealed potent neuroprotective and neuroregenerative properties of immunophilin ligands in both culture and animal models [6]. However, the mechanisms underlying these trophic effects are still largely unknown, though the role of FKBP52 has been implicated in a number of studies [7].…”