scy-635 and alisporivir

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

The current standard of care for hepatitis C virus (HCV) infection, pegylated alpha interferon in combination with ribavirin, has a limited response rate and adverse side effects. Drugs targeting viral proteins are in clinical development, but they suffer from the development of high viral resistance. The inhibition of cellular proteins that are essential for viral amplification is thought to have a higher barrier to the emergence of resistance. Three cyclophilin inhibitors, the cyclosporine analogs DEBIO-025, SCY635, and NIM811, have shown promising results for the treatment of HCV infection in early clinical trials. In this study, we investigated the frequency and mechanism of resistance to cyclosporine (CsA), NIM811, and a structurally unrelated cyclophilin inhibitor, SFA-1, in replicon-containing Huh7 cells. Cross-resistance between all clones was observed. NIM811-resistant clones were selected only after obtaining initial resistance to either CsA or SFA-1. The time required to select resistance against cyclophilin inhibitors was significantly longer than that required for resistance selection against viral protein inhibitors, and the achievable resistance level was substantially lower. Resistance to cyclophilin inhibitors was mediated by amino acid substitutions in NS3, NS5A, and NS5B, with NS5A mutations conferring the majority of resistance. Mutation D320E in NS5A mediated most of the resistance conferred by NS5A. Taken together, the results indicate that there is a very low frequency and level of resistance to cyclophilin-binding drugs mediated by amino acid substitutions in three viral proteins. The interaction of cyclophilin with NS5A seems to be the most critical, since the NS5A mutations have the largest impact on resistance.

Topics: Antiviral Agents; Cell Line; Cyclophilins; Cyclosporine; Cyclosporins; Drug Resistance, Viral; Enzyme Inhibitors; Hepacivirus; Humans; Lactones; Mutagenesis, Site-Directed; Replicon; RNA, Viral; Spiro Compounds; Transfection; Viral Nonstructural Proteins