Cyclosporin A-Derivative 1

HCV infection is the primary cause of chronic liver disease. Host cell cyclophilins (Cyps) are essential for efficient HCV replication in hepatocytes, and thus Cyps are regarded as a new target for anti-HCV therapy. Alisporivir (Debio-025), a non-immunosuppressive cyclosporine A derivative that selectively inhibits Cyps, is being developed by Debiopharm SA for the potential oral treatment of HCV infection. In the HCV subgenomic replicon system, alisporivir suppressed viral replication more potently than cyclosporine A. A phase II clinical trial demonstrated that treatment with alisporivir alone or combined with PEGylated IFNalpha2a reduced the viral load in patients with chronic HCV infection. The drug was also generally well tolerated. In contrast, a phase I trial of alisporivir monotherapy in patients with HIV-1 infection suggested that the drug has a limited effect on HIV-1 viral load. Alisporivir was also investigated in animal models of muscular dystrophy, acute myocardial infarction and brain disorders. At the time of publication, two phase II trials, evaluating alisporivir alone and in combination with PEGylated IFNalpha2a or with PEGylated IFNalpha2a and ribavirin, were ongoing in treatment-naïve patients with HCV-1 infection and in patients with chronic HCV-1 infection who were prior non-responders to PEGylated IFNalpha or ribavirin.

FR901459, a product of the fungus Stachybotrys chartarum No. 19392, is a derivative of cyclosporin A (CsA) and a powerful immunosuppressant that binds cyclophilin. Recently, it was reported that CsA was effective against hepatitis C virus (HCV). However, FR901459 lacks active moieties, which are essential for synthesizing more potent and safer derivatives of this anti-HCV agent. Here we identified an actinomycete strain (designated 7887) that was capable of efficient bioconversion of FR901459. Structural elucidation of the isolated bioconversion products (1-7) revealed that compounds 1-4 were mono-hydroxylated at the position of 1-MeBmt or 9-MeLeu, whereas compounds 5-7 were bis-hydroxylated at both positions. The results of morphological and chemical characterization, as well as phylogenetic analysis of 16S ribosomal DNA (rDNA), suggested that strain 7887 belonged to the genus Lentzea. Comparison of the FR901459 conversion activity of strain 7887 with several other Lentzea strains revealed that although all examined strains metabolized FR901459, strain 7887 had a characteristic profile with respect to bioconversion products. Taken together, these findings suggest that strain 7887 can be used to derivative FR901459 to produce a chemical template for further chemical modifications that may provide more effective and safer anti-HCV drugs.

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.