RT Journal Article
SR Electronic
T1 Genetically Engineered Analogs of Ascomycin for Nerve Regeneration
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1278
OP 1285
DO 10.1124/jpet.102.034264
VO 302
IS 3
A1 W. P. Revill
A1 J. Voda
A1 C. R. Reeves
A1 L. Chung
A1 A. Schirmer
A1 G. Ashley
A1 J. R. Carney
A1 M. Fardis
A1 C. W. Carreras
A1 Y. Zhou
A1 L. Feng
A1 E. Tucker
A1 D. Robinson
A1 B. G. Gold
YR 2002
UL http://jpet.aspetjournals.org/content/302/3/1278.abstract
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