Antamanide is a cyclic decapeptide derived from the fungus Amanita phalloides. 
Here we show that antamanide inhibits the mitochondrial permeability transition 
pore, a central effector of cell death induction, by targeting the pore 
regulator cyclophilin D. Indeed, (i) permeability transition pore inhibition by 
antamanide is not additive with the cyclophilin D-binding drug cyclosporin A, 
(ii) the inhibitory action of antamanide on the pore requires phosphate, as 
previously shown for cyclosporin A; (iii) antamanide is ineffective in 
mitochondria or cells derived from cyclophilin D null animals, and (iv) 
abolishes CyP-D peptidyl-prolyl cis-trans isomerase activity. Permeability 
transition pore inhibition by antamanide needs two critical residues in the 
peptide ring, Phe6 and Phe9, and is additive with ubiquinone 0, which acts on 
the pore in a cyclophilin D-independent fashion. Antamanide also abrogates 
mitochondrial depolarization and the ensuing cell death caused by two 
well-characterized pore inducers, clotrimazole and a hexokinase II N-terminal 
peptide. Our findings have implications for the comprehension of cyclophilin D 
activity on the permeability transition pore and for the development of novel 
pore-targeting drugs exploitable as cell death inhibitors.