ROLES OF PEPTIDYL-PROLYL CIS-TRANS ISOMERASE AND CALCINEURIN IN THE MECHANISMS OF ANTIMALARIAL ACTION OF CYCLOSPORINE-A, FK506, AND RAPAMYCIN

The immunosuppressive peptide cyclosporin A inhibits the growth of mal aria parasites in vitro and in vivo, but little is known about its mec hanism of antimalarial action. The immunosuppressive action of cyclosp orin A is believed to result from binding of the drug to cyclophilins (intracellular peptidyl-prolyl cis-trans isomerases), and inhibition o f the protein phosphatase calcineurin by the cyclosporin A-cyclophilin complex. Two immunosuppressive macrolides, FK506 and rapamycin, bind to a distinct isomerase, FKBP12, and the FK506-FKBP complex also inhib its calcineurin. Calcineurin itself is apparently involved in signal t ransduction between the T-cell membrane and nucleus, and its inhibitio n blocks T-cell activation. Rapamycin inhibits a later step in T-cell proliferation. Peptidyl-prolyl cis-trans isomerase activity was detect ed in extracts of Plasmodium falciparum. It was completely inhibited b y concentrations of cyclosporin A above 0.1 mu M, but not by FK506 or rapamycin, and probably represented one or more cyclophilins. Comparis on of the antimalarial and anti-isomerase activities of a series of cy closporin analogues failed to reveal a correlation between the two pro perties. Cyclosporin A and its more active 8'-oxymethyl-dihydro-deriva tive, in combination with the cyclophilin-containing P. falciparum ext ract, inhibited the protein phosphatase activity of bovine calcineurin . Therefore inhibition of a putative P. falciparum calcineurin by a co mplex of CsA and cyclophilin might be responsible for the antimalarial action of the drug. The most active cyclosporin, however, was a 3'- k eto-derivative of cyclosporin D (SDZ PSC-833) which inhibited P. falci parum growth with a 50% inhibitory concentration (IC50) of 0.032 mu M (compared with 0.30 mu M for cyclosporin A), but was a poor inhibitor of the parasite isomerase. 3'-Keto-cyclosporin D has negligible immuno suppressive activity, but it strongly inhibits the P-glycoprotein of m ulti-drug resistant mammalian tumour cells. FK506 and rapamycin were a lso active antimalarials (IC50 of 1.9 and 2.6 mu M, respectively) but in the absence of detectable FKBP in P. falciparum extracts, their mec hanisms of antimalarial action remain unclear.