Gossypol inhibits calcineurin phosphatase activity at multiple sites.

摘要: Abstract Calcineurin, the Ca2+/calmodulin-dependant serine/threonine phosphatase is target for immunosuppressant drugs FK506 and cyclosporine-A. These established calcineurin inhibitors each require an immunophilin protein cofactor. Gossypol, a polyphenol produced by cotton plant, inhibits (IC50 = 15 μM), in noncompetitive, reversible manner, independent of any We found that gossypol acts at least two mechanisms to inhibit activity. A calmodulin-independent form was less sensitive inhibition than native (IC50 = 41 18 μM, respectively) indicating may interfere with calmodulin binding. fluorescence polarization based assay demonstrated 100 μM reduced affinity (from Kd = 2.4 250 nM). Inhibition activity could not be overcome adding excess or testing toward site different from calmodulin-binding site. Gossypol decreased immunosuppressant/immunophilin complexes only presence calmodulin, blocks effects binding calcineurin. In addition, had stimulatory effect on absence possibly mimetic effect. exists enantiomeric forms which are reported have potency cell toxicity. (+) (−) equivalent activity, The via multiple sites without stereo-specificity indicates specific inhibitor.