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.

Immunophilin Dysfunction and Neuropathology

“…The elongation rate described for these compound is similar to that of FKBP12 ligands, such as FK506, V-10,367, and V-13,449, however any of these drugs bind to FKBP12, indicating that other IPs might participate in this process [12]. In particular, the non-FKBP12 ligand V-13,670, accelerates functional recovery of neurons and nerve regeneration in the rat sciatic nerve crush model [12]. FK506 and nonimmunosuppressant compounds, such as GPI1046 and L685818 are IPLs that specifically bind to IPs like FKBP12 [13,14], also exert neurotrophic properties in neural injuries.…”

Immunophilin Dysfunction and Neuropathology

“…The elongation rate described for these compound is similar to that of FKBP12 ligands, such as FK506, V-10,367, and V-13,449, however any of these drugs bind to FKBP12, indicating that other IPs might participate in this process [12]. In particular, the non-FKBP12 ligand V-13,670, accelerates functional recovery of neurons and nerve regeneration in the rat sciatic nerve crush model [12]. FK506 and nonimmunosuppressant compounds, such as GPI1046 and L685818 are IPLs that specifically bind to IPs like FKBP12 [13,14], also exert neurotrophic properties in neural injuries.…”

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

“…[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. [10,18] As a new entry into this molecular landscape, the nocardiopsins are the first natural product examples of this biosynthetic structure class to be reported in over a decade (Figure 2).…”

“…[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.…”

Calcineurin inhibition enhances motor neuron survival following injury

“…Due to the array of potential cellular interaction targets for both CsA and FK‐506, several possible mechanisms of neuronal survival effects exist beyond that of calcineurin inhibition. Recently, several calcineurin‐independent signalling pathways have been suggested as possible means by which CsA and FK‐506 exert their neuroprotective effects using non‐immunosuppressive (calcineurin‐independent) immunophilin ligands such as GPI‐1046 and V‐10,367 [3, 14, 39–41]. In addition, an alternative calcineurin‐independent model of FK‐506‐mediated neuritic outgrowth has recently been proposed [42, 43].…”

Immunophilin Dysfunction and Neuropathology

“…The elongation rate described for these compound is similar to that of FKBP12 ligands, such as FK506, V-10,367, and V-13,449, however any of these drugs bind to FKBP12, indicating that other IPs might participate in this process [12]. In particular, the non-FKBP12 ligand V-13,670, accelerates functional recovery of neurons and nerve regeneration in the rat sciatic nerve crush model [12]. FK506 and nonimmunosuppressant compounds, such as GPI1046 and L685818 are IPLs that specifically bind to IPs like FKBP12 [13,14], also exert neurotrophic properties in neural injuries.…”

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

“…[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. [10,18] As a new entry into this molecular landscape, the nocardiopsins are the first natural product examples of this biosynthetic structure class to be reported in over a decade (Figure 2).…”

“…[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.…”

Calcineurin inhibition enhances motor neuron survival following injury

“…Due to the array of potential cellular interaction targets for both CsA and FK‐506, several possible mechanisms of neuronal survival effects exist beyond that of calcineurin inhibition. Recently, several calcineurin‐independent signalling pathways have been suggested as possible means by which CsA and FK‐506 exert their neuroprotective effects using non‐immunosuppressive (calcineurin‐independent) immunophilin ligands such as GPI‐1046 and V‐10,367 [3, 14, 39–41]. In addition, an alternative calcineurin‐independent model of FK‐506‐mediated neuritic outgrowth has recently been proposed [42, 43].…”

Immunophilin Dysfunction and Neuropathology

“…The elongation rate described for these compound is similar to that of FKBP12 ligands, such as FK506, V-10,367, and V-13,449, however any of these drugs bind to FKBP12, indicating that other IPs might participate in this process [12]. In particular, the non-FKBP12 ligand V-13,670, accelerates functional recovery of neurons and nerve regeneration in the rat sciatic nerve crush model [12]. FK506 and nonimmunosuppressant compounds, such as GPI1046 and L685818 are IPLs that specifically bind to IPs like FKBP12 [13,14], also exert neurotrophic properties in neural injuries.…”

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

“…[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. [10,18] As a new entry into this molecular landscape, the nocardiopsins are the first natural product examples of this biosynthetic structure class to be reported in over a decade (Figure 2).…”

“…[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.…”

Calcineurin inhibition enhances motor neuron survival following injury

“…Due to the array of potential cellular interaction targets for both CsA and FK‐506, several possible mechanisms of neuronal survival effects exist beyond that of calcineurin inhibition. Recently, several calcineurin‐independent signalling pathways have been suggested as possible means by which CsA and FK‐506 exert their neuroprotective effects using non‐immunosuppressive (calcineurin‐independent) immunophilin ligands such as GPI‐1046 and V‐10,367 [3, 14, 39–41]. In addition, an alternative calcineurin‐independent model of FK‐506‐mediated neuritic outgrowth has recently been proposed [42, 43].…”