Cyclosporins: lack of correlation between antischistosomal properties and inhibition of cyclophilin isomerase activity.
The immunosuppressive fungal products cyclosporin A (CsA) and FK506 bind with high affinity to intracellular receptor proteins: cyclophilin (CYP) is one of the receptors for CsA and FK506-binding protein (FKBP) is one of the receptors for FK506. These proteins catalyze the in vitro isomerization from a cis to a trans conformation of peptidyl-prolyl bonds in oligopeptides. The relative importance of the peptidyl-prolyl cis-trans isomerase (PPI ase) activity of CYP compared to FKBP in schistosomes is not known. Here, we examine the effects of CsA and FK506 and show that the former inhibits PPIase activity in schistosome extracts, whereas the latter does not. Since CsA is specific for the CYP protein, this result is indicative of the fact that the PPIase activity in the parasite is mostly attributable to CYP. The observation that CsA was significantly more effective than FK506 as an antischistosomal agent, both in vivo and in vitro raises the possibility that killing of schistosomes is caused by the inhibition of schistosome CYP PPIase. We compared a number of Cs analogs for their antischistosomal effects and for the inhibition of CYP PPIase, but were unable to find a correlation between the two properties. We therefore conclude that the lethal effect of CsA is not directly linked to the inhibition of the enzymatic activity of schistosome CYPs.
Khattab
A
A
Istituto di Biologia Cellulare, Consiglio Nazionale delle Ricerche, 43 Viale Marx, Rome, 00137, Italy.
Pica-Mattoccia
L
L
Klinkert
M Q
MQ
Wenger
R
R
Cioli
D
D
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007700:Kinetics; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology; D012556:Schistosomicides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D003524:Cyclosporins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D012556:Schistosomicides; D016572:Cyclosporine; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus