PT  - JOURNAL ARTICLE
AU  - W. P. Revill
AU  - J. Voda
AU  - C. R. Reeves
AU  - L. Chung
AU  - A. Schirmer
AU  - G. Ashley
AU  - J. R. Carney
AU  - M. Fardis
AU  - C. W. Carreras
AU  - Y. Zhou
AU  - L. Feng
AU  - E. Tucker
AU  - D. Robinson
AU  - B. G. Gold
TI  - Genetically Engineered Analogs of Ascomycin for Nerve Regeneration
AID  - 10.1124/jpet.102.034264
DP  - 2002 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1278--1285
VI  - 302
IP  - 3
4099  - http://jpet.aspetjournals.org/content/302/3/1278.short
4100  - http://jpet.aspetjournals.org/content/302/3/1278.full
SO  - J Pharmacol Exp Ther2002 Sep 01; 302
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics