EXPERIMENTAL PARASITOLOGY 90, 103–109 (1998) ARTICLE NO. PR984307 Cyclosporins: Lack of Correlation between Antischistosomal Properties and Inhibition of Cyclophilin Isomerase Activity A. Khattab, L. Pica-Mattoccia, M. Q. Klinkert, 1 R. Wenger,* ,2 and D. Cioli Istituto di Biologia Cellulare, Consiglio Nazionale delle Ricerche, 43 Viale Marx, 00137 Rome, Italy; and *Novartis Pharma AG, Basel, Switzerland Khattab, A., Pica-Mattoccia, L., Klinkert, M. Q., Wenger, R., and INTRODUCTION Cioli, D. 1998. Cyclosporins: Lack of correlation between antischisto- somal properties and inhibition of cyclophilin isomerase activity. Exper- imental Parasitology 90, 103–109. The immunosuppressive fungal products cyclosporin A (CsA) and FK506 bind with high affinity to intracellular receptor proteins: cyclophilin (CYP) is one of the receptors Cyclosporin A (CsA) is a neutral lipophilic cyclic peptide for CsA and FK506-binding protein (FKBP) is one of the receptors of fungal origin consisting of 11 amino acids and exhibiting for FK506. These proteins catalyze the in vitro isomerization from a different biological properties. Its best known activity is cis to a trans conformation of peptidyl-prolyl bonds in oligopeptides. the immunosuppressive effect exerted through inhibition of The relative importance of the peptidyl-prolyl cis-trans isomerase (PPI- ase) activity of CYP compared to FKBP in schistosomes is not known. immunocompetent T lymphocytes (reviewed in Borel et al. Here, we examine the effects of CsA and FK506 and show that the 1996). Unexpectedly, CsA also possesses antiparasitic activi- former inhibits PPIase activity in schistosome extracts, whereas the ties against schistosomes, plasmodia, nematodes, and ces- latter does not. Since CsA is specific for the CYP protein, this result todes (Bueding et al. 1981; Chappell and Thompson 1988; is indicative of the fact that the PPIase activity in the parasite is mostly reviewed in Bell et al. 1996). It is well documented that the attributable to CYP. The observation that CsA was significantly more effective than FK506 as an antischistosomal agent, both in vivo and antiparasitic activity is not related to the immunosuppressive in vitro raises the possibility that killing of schistosomes is caused by properties, based on the existence of CsA analogs that are the inhibition of schistosome CYP PPIase. We compared a number of poor immunosuppressants but exert antiparasitic effects Cs analogs for their antischistosomal effects and for the inhibition of (Chappell et al. 1987), and on the fact that parasites can be CYP PPIase, but were unable to find a correlation between the two killed in vitro, that is, in the absence of host factors (Brannan properties. We therefore conclude that the lethal effect of CsA is not directly linked to the inhibition of the enzymatic activity of schistosome et al. 1989). CYPs.  1998 Academic Press In contrast to the vast amount of knowledge on the biologi- Index Descriptors and Abbreviations: Schistosoma mansoni; cal and clinical aspects of CsA immunosuppressive activity, cyclosporins; FK506; PPIase. the mechanism through which the antiparasitic effect is me- diated still remains elusive. We have approached the problem by examining the molecular interactions of CsA with parasite constituents. Proteins that bind CsA with high affinity (cyclophilins, CYPs) are present in schistosomes as in all eukaryotic cells and can be thought of as intracellular recep- tors for CsA. The molecular and biochemical properties of 1 To whom correspondence should be addressed at Mo-Quen Klinkert Consiglio Nazionale delle Ricerche, Istituto di Biologia Cellulare, Viale schistosome CYPs have been previously reported (Argaet Marx 43, 00137 Rome, Italy. Fax: +39-6-8273287. and Mitchell 1992; Klinkert et al. 1995, 1996, Kiang et 2 Present address: Wenger Chemtech, CH-4125 Riehen, Switzerland. al. 1996). 103 0014-4894/98 $25.00 Copyright  1998 by Academic Press All rights of reproduction in any form reserved.