Preclinical Characterization of PF-00868554, a Potent Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase

Department of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, San Diego, CA 92121, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 04/2009; 53(6):2544-52. DOI: 10.1128/AAC.01599-08
Source: PubMed


PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to the thumb base domain of the protein. It is a potent and selective inhibitor, with a mean 50% inhibitory concentration of 0.019 microM against genotype 1 polymerases and a mean 50% effective concentration (EC(50)) of 0.075 microM against the genotype 1b-Con1 replicon. To determine the in vitro antiviral activity of PF-00868554 against various HCV strains, a panel of chimeric replicons was generated, in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the 1b-Con1 subgenomic reporter replicon. Our results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1a and 1b replicons, with an overall mean EC(50) of 0.059 microM. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 microM). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins. An in vitro resistance study of PF-00868554 identified M423T as the predominant resistance mutation, resulting in a 761-fold reduction in susceptibility to PF-00868554 but no change in susceptibility to alpha interferon and a polymerase inhibitor that binds to a different region. PF-00868554 also showed good pharmacokinetic properties in preclinical animal species. Our results demonstrate that PF-00868554 has potent and broad-spectrum antiviral activity against genotype 1 HCV strains, supporting its use as an oral antiviral agent in HCV-infected patients.

Download full-text


Available from: M. Angelica Linton, Apr 15, 2015
  • Source
    • "utation , resulting in a 761 - fold reduction in susceptibility to filibuvir , but no change in susceptibility to IFN - α and a polymerase inhibitor that binds to a different region . Filibuvir also showed good pharmacokinetic properties in preclinical animal species , revealing promising oral bioavailability in both rodent and nonrodent species ( Shi et al . , 2009 ) . Also , filibuvir seemed not to affect any of the major CYP isoforms ( IC 50 >30 µmol / L for 1A2 , 2C8 , 2D6 , 3A4 , 2C9 , and 2C19 ) ( Li et al . , 2009 ) ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-α (PEG-IFN α) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs.
    Full-text · Article · Jan 2012 · Journal of Zhejiang University SCIENCE B
  • Source
    • "During in-vitro resistance study of PF-00868554, amino acid (AA) changes were recognized at the allosteric site of the polymerase, comprising M423T/V/I, M426T, and I482T, but switching at M423 resulted in relatively much resistance than others. Notably, replicons enclosing these resistance changes have found no cross-resistance with IFN and other polymerase inhibitors, sustaining the make use of PF-00868554 in combination therapies [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT: Hepatitis C virus (HCV) infection is a major worldwide problem causes acute and chronic HCV infection. Current treatment of HCV includes pegylated interferon-α (PEG IFN- α) plus ribavirin (RBV) which has significant side effects depending upon the type of genotype. Currently, there is a need to develop antiviral agents, both from synthetic chemistry and Herbal sources. In the last decade, various novel HCV replication, helicase and entry inhibitors have been synthesized and some of which have been entered in different phases of clinical trials. Successful results have been acquired by executing combinational therapy of compounds with standard regime in different HCV replicons. Even though, diverse groups of compounds have been described as antiviral targets against HCV via Specifically Targeted Antiviral Therapy for hepatitis C (STAT-C) approach (in which compounds are designed to directly block HCV or host proteins concerned in HCV replication), still there is a need to improve the properties of existing antiviral compounds. In this review, we sum up potent antiviral compounds against entry, unwinding and replication of HCV and discussed their activity in combination with standard therapy. Conclusively, further innovative research on chemical compounds will lead to consistent standard therapy with fewer side effects.
    Full-text · Article · Jun 2011 · Genetic Vaccines and Therapy
  • Source
    • "NS3 protease and NS5B polymerase enzymes, essential for HCV replication, are primary targets. Results for inhibitors targeting these enzymes (combined with pegIFN + RBV) are positive in clinical trials [11, 96, 97] and preclinical studies [98–100]. The most promising of these are the protease inhibitors telaprevir and boceprevir, which are expected to be approved this year [101, 102]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies.
    Full-text · Article · Mar 2011 · Current HIV/AIDS Reports
Show more