mk-0608 and Hepatitis-C

In the last few months, a new Zika virus (ZIKV) outbreak evolved in America. In accordance, World Health Organization (WHO) in February 2016 declared it as Public Health Emergency of International Concern (PHEIC). ZIKV infection was reported in more than 60 countries and the disease was spreading since 2007 but with little momentum. Many antiviral drugs are available in market or in laboratories under clinical trials, could affect ZIKV infection. In silico docking study were performed on the ZIKV polymerase to test some of Hepatitis C Virus (HCV) drugs (approved and in clinical trials). The results show potency of almost all of the studied compounds on ZIKV polymerase and hence inhibiting the propagation of the disease. In addition, the study suggested two nucleotide inhibitors (IDX-184 and MK0608) that may be tested as drugs against ZIKV infection. J. Med. Virol. 88:2044-2051, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Antiviral Agents; Clinical Trials as Topic; Computer Simulation; Drug Discovery; Enzyme Inhibitors; Guanosine Monophosphate; Hepacivirus; Hepatitis C; Humans; Molecular Docking Simulation; RNA-Dependent RNA Polymerase; Tubercidin; Zika Virus; Zika Virus Infection

Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.

Topics: Animals; Antiviral Agents; Dogs; Enzyme Inhibitors; Hepacivirus; Hepatitis C; Humans; Nucleosides; Organophosphorus Compounds; Rats; Viral Load; Viral Nonstructural Proteins

Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide and is associated with an increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Currently approved therapies to treat HCV infection consist of combinations of pegylated alpha interferon and ribavirin which result in a sustained viral response in 40 to 60% of patients. Efforts to develop improved therapies include the development of direct inhibitors of virally encoded enzymes such as the viral RNA-dependent RNA polymerase. A nucleoside analog, 2'-C-methyl-7-deaza-adenosine (MK-0608), has been shown to inhibit viral RNA replication in the subgenomic HCV genotype 1b replicon, with a 50% effective concentration (EC(50)) of 0.3 microM (EC(90) = 1.3 microM). To determine efficacy in vivo, MK-0608 was administered to HCV-infected chimpanzees, resulting in dose- and time-dependent decreases in plasma viral loads. In separate experiments, chimpanzees dosed for 7 days with MK-0608 at 0.2 and 2 mg per kg of body weight per day by intravenous administration experienced average reductions in viral load of 1.0 and >5 log(10) IU/ml, respectively. Two other HCV-infected chimpanzees received daily doses of 1 mg MK-0608 per kg via oral administration. After 37 days of oral dosing, one chimpanzee with a high starting viral load experienced a reduction in viral load of 4.6 log(10), and the viral load in the other chimpanzee fell below the limit of quantification (LOQ) of the HCV TaqMan assay (20 IU/ml). Importantly, viral load remained below the LOQ throughout the duration of dosing and for at least 12 days after dosing ended. The results demonstrate a robust antiviral effect on the administration of MK-0608 to HCV-infected chimpanzees.

Topics: Animals; Antiviral Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Hepacivirus; Hepatitis C; Inhibitory Concentration 50; Molecular Structure; Nucleosides; Pan troglodytes; RNA, Viral; Time Factors; Tubercidin; Viral Load