scy-635 and Hepatitis-C

This article highlights a unique time in the history of hepatitis C therapy. In the last few years new families of direct-acting antivirals have emerged, that block different viral proteins to interrupt viral replication, such as protease, NS5A inhibitors, and NS5B inhibitors. There are few host-targeted agents in development; currently cyclophilin inhibitors are the only host-targeted agents in advanced development. One of these new agents has now progressed to phase 3 clinical trials; in this review article their potential role as a future therapy to cure hepatitis C is discussed.

Topics: Antiviral Agents; Cyclophilins; Cyclosporine; Cyclosporins; Drug Therapy, Combination; Enzyme Inhibitors; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Viral Nonstructural Proteins

The percentage of patients chronically infected with hepatitis C virus (HCV) who have reached sustained antiviral response has increased since the introduction of the pegylated interferon-alpha (pIFNa) and ribavirin (RBV) treatment. However, the current standard pIFNa/RBV therapy not only has a low success rate (about 50%) but is often associated with serious side effects. Thus, there is an urgent need for the development of new anti-HCV agents. Cyclophilin (Cyp) inhibitors are among the most promising of the new anti-HCV agents under development. Recent clinical studies demonstrate that Cyp inhibitors are potent anti-HCV drugs, with a novel mechanism of action and efficacy profiles that make them attractive candidates for combination with current and future HCV treatments.

Topics: Antiviral Agents; Cyclophilins; Cyclosporine; Cyclosporins; Drug Discovery; Hepacivirus; Hepatitis C; Humans; Virus Replication

The cyclophilins are widely expressed enzymes that catalyze the interconversion of the cis and trans peptide bonds of prolines. The immunosuppressive natural products cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the cyclophilins. Chemical modification of both the cyclosporine and sanglifehrin scaffolds has produced many analogues that inhibit cyclophilins in vitro but have reduced immunosuppressive properties. Three nonimmunosuppressive cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated clinical efficacy for the treatment of hepatitis C infection. Additional candidates are in various stages of preclinical development for the treatment of hepatitis C or myocardial reperfusion injury. Recent publications suggest that cyclophilin inhibitors may have utility for the treatment of diverse viral infections, inflammatory indications, and cancer. In this review, we document the structure-activity relationships of the nonimmunosuppressive cyclosporins and sanglifehrins in clinical and preclinical development. Aspects of the pharmacokinetic behavior and chemical biology of these drug candidates are also described.

Topics: Antiviral Agents; Chemistry, Pharmaceutical; Cyclophilins; Cyclosporine; Cyclosporins; Enzyme Inhibitors; Hepacivirus; Hepatitis C; Host-Pathogen Interactions; Humans; Lactones; Models, Molecular; Molecular Structure; Protein Binding; Protein Structure, Tertiary; Spiro Compounds; Structure-Activity Relationship

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

Topics: Animals; Antiviral Agents; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Cyclophilins; Cyclosporine; Cyclosporins; Dogs; Hepacivirus; Hepatitis C; Humans; Hydrophobic and Hydrophilic Interactions; Immunosuppressive Agents; Liver-Specific Organic Anion Transporter 1; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Peptidyl-Prolyl Isomerase F; Rats; Structure-Activity Relationship; Virus Replication

Cyclophilin inhibitors are being developed for treatment of hepatitis C virus (HCV) infection. They are believed to inhibit the HCV replication complex. We investigated whether cyclophilin inhibitors interact with interferon (IFN) signaling in cultured cells infected with HCV.. We used immunoblot assays to compare expression of IFN-stimulated genes (ISGs) and of components of IFN signaling in HCV-infected and uninfected cells.. Incubation with IFN alfa induced expression of ISGs in noninfected cells and, to a lesser extent, in HCV-infected cells; addition of the cyclophilin inhibitor SCY-635 restored expression of ISG products in HCV-infected cells. SCY-635 reduced phosphorylation of double-strand RNA-dependent protein kinase (PKR) and its downstream factor eIF2α; the phosphorylated forms of these proteins are negative regulators of ISG translation. Cyclophilin A interacted physically with PKR; this interaction was disrupted by SCY-635. SCY-635 also suppressed PKR-mediated formation of stress granules. Cyclophilin inhibitors were found to inhibit PKR phosphorylation and stress granule formation in HCV-infected and uninfected cells.. In cultured cells, cyclophilin inhibitors reverse the attenuation of the IFN response by HCV, in addition to their effects on HCV replication complex. Cyclophilin A regulation of PKR has been proposed as a mechanism for observed effects of cyclophilin inhibitors on IFN signaling. We found that cyclophilin inhibitors reduce phosphorylation of PKR and eIF2α during HCV infection to allow for translation of ISG products. Proteins in this pathway might be developed as targets for treatment of HCV infection.

Topics: Antiviral Agents; Cell Line, Tumor; Cyclophilin A; Cyclosporins; Cytoplasmic Granules; eIF-2 Kinase; Enzyme Inhibitors; Eukaryotic Initiation Factor-2; Gene Expression Regulation; Hepacivirus; Hepatitis C; Humans; Interferon Regulatory Factors; Interferon-alpha; Liver; Phosphorylation; RNA, Messenger; Signal Transduction

SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 microM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV.

Topics: Animals; Antiviral Agents; Cell Line; Cells, Cultured; Cyclophilin A; Cyclosporins; Dogs; Dose-Response Relationship, Drug; Enzyme Activation; Haplorhini; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Immunosuppressive Agents; Interleukin-2; Jurkat Cells; Leukocytes, Mononuclear; Mice; Molecular Structure; Rats; RNA, Viral; Virus Replication