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Genetically engineered analogs of ascomycin for nerve regeneration
- Source :
- The Journal of pharmacology and experimental therapeutics. 302(3)
- Publication Year :
- 2002
-
Abstract
- 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.
- Subjects :
- Nervous system
Neurite
Nerve Crush
T-Lymphocytes
Genetic Vectors
Biology
Protein Engineering
Hippocampus
Tacrolimus
Cell Line
Acetyltransferases
Gene cluster
medicine
Neurites
Animals
Humans
Ascomycin
Ternary complex
Pharmacology
Regeneration (biology)
Calcineurin
Sciatic Nerve
Recombinant Proteins
Streptomyces
Nerve Regeneration
Rats
FKBP
medicine.anatomical_structure
Biochemistry
Molecular Medicine
Immunosuppressive Agents
medicine.drug
Protein Binding
Subjects
Details
- ISSN :
- 00223565
- Volume :
- 302
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Accession number :
- edsair.doi.dedup.....5c749f7be5f3552b34e1801200929036