Genetically Engineered Analogs of Ascomycin for Nerve Regeneration

The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/520-calcineurin ternary complex. They also have calcineurin-independent neuroregenerative properties in cell culture and ani...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2002-09, Vol.302 (3), p.1278-1285
Main Authors: Revill, W P, Voda, J, Reeves, C R, Chung, L, Schirmer, A, Ashley, G, Carney, J R, Fardis, M, Carreras, C W, Zhou, Y, Feng, L, Tucker, E, Robinson, D, Gold, B G
Format: Article
Language:English
Subjects:
Acetyltransferases - genetics
Acetyltransferases - metabolism
Animals
Calcineurin - metabolism
Cell Line
Genetic Vectors
Hippocampus - cytology
Hippocampus - drug effects
Humans
Immunosuppressive Agents - pharmacology
Nerve Crush
Nerve Regeneration - drug effects
Neurites - drug effects
Protein Binding
Protein Engineering
Rats
Recombinant Proteins - pharmacology
Sciatic Nerve - drug effects
Sciatic Nerve - pathology
Streptomyces - genetics
Streptomyces - metabolism
T-Lymphocytes - drug effects
T-Lymphocytes - metabolism
Tacrolimus - analogs & derivatives
Tacrolimus - pharmacology
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Summary:The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/520-calcineurin ternary complex. They also have calcineurin-independent neuroregenerative properties in cell culture and animal models of nervous system disorders. Based on the crystal structure of the FKBP12-FK506-calcineurin complex, we deduced that the 13- and 15-methoxy groups of FK506 or FK520 are important for inhibition of calcineurin phosphatase but not for binding to FKBP12. By genetic modification of the FK520 gene cluster, we generated 13- and 15-desmethoxy analogs of FK520 that contain hydrogen, methyl, or ethyl instead of methoxy at one or both of these positions. These analogs bind FKBP12 tightly, have decreased calcineurin phosphatase inhibition and immunosuppressive properties, and enhance neurite outgrowth in cell cultures. A representative compound was also shown to accelerate nerve regeneration and functional recovery in the rat sciatic nerve crush model.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.102.034264