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Genetically engineered analogs of ascomycin for nerve regeneration
W P Revill1, J Voda, C R Reeves
1Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA. revill@kosan.com
The Journal of Pharmacology and Experimental Therapeutics
|August 17, 2002
Summary
New FK520 analogs, lacking methoxy groups, show reduced immunosuppression but enhanced nerve regeneration, accelerating recovery in animal models.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- FK506 (tacrolimus) and FK520 (ascomycin) are immunosuppressants inhibiting calcineurin phosphatase via an FKBP12-drug-calcineurin complex.
- These compounds also exhibit calcineurin-independent neuroregenerative effects in various models.
Purpose of the Study:
- To investigate the role of FK506/520 methoxy groups in calcineurin inhibition and FKBP12 binding.
- To develop FK520 analogs with modified immunosuppressive and enhanced neuroregenerative properties.
Main Methods:
- Genetic modification of the FK520 gene cluster to create 13- and 15-desmethoxy analogs.
- Assessing FKBP12 binding affinity, calcineurin phosphatase inhibition, and immunosuppressive activity.
- Evaluating neurite outgrowth in cell cultures and nerve regeneration in a rat sciatic nerve crush model.
Main Results:
- Generated FK520 analogs with hydrogen, methyl, or ethyl substitutions for methoxy groups.
- Analogs exhibited tight FKBP12 binding but reduced calcineurin inhibition and immunosuppression.
- These analogs promoted neurite outgrowth in vitro and accelerated nerve regeneration and functional recovery in vivo.
Conclusions:
- The 13- and 15-methoxy groups are crucial for calcineurin phosphatase inhibition but not FKBP12 binding.
- FK520 analogs with modified methoxy groups offer a potential therapeutic strategy for nerve regeneration with reduced immunosuppressive side effects.
