An estimated 170 million individuals worldwide are infected with hepatitis C virus (HCV), a serious cause of chronic liver disease. Current interferon-based therapy for treating HCV infection has an unsatisfactory cure rate, and the development of more efficient drugs is needed. During the early stages of HCV infections, various host genes are differentially regulated, and it is possible that inhibition of host proteins affords a therapeutic strategy for treatment of HCV infection. Using an HCV subgenomic replicon cell culture system, here we have identified, from a secondary fungal metabolite, a lipophilic long-chain base compound, NA255 (1), a previously unknown small-molecule HCV replication inhibitor. NA255 prevents the de novo synthesis of sphingolipids, major lipid raft components, thereby inhibiting serine palmitoyltransferase, and it disrupts the association among HCV nonstructural (NS) viral proteins on the lipid rafts. Furthermore, we found that NS5B protein has a sphingolipid-binding motif in its molecular structure and that the domain was able to directly interact with sphingomyelin. Thus, NA255 is a new anti-HCV replication inhibitor that targets host lipid rafts, suggesting that inhibition of sphingolipid metabolism may provide a new therapeutic strategy for treatment of HCV infection.
Most acute hepatitis C virus (HCV) infections become chronic and some progress to liver cirrhosis or hepatocellular carcinoma. Standard therapy involves an interferon (IFN)-α-based regimen, and efficacy of therapy has been significantly improved by the development of protease inhibitors. However, several issues remain concerning the injectable form and the side effects of IFN. Here, we report an orally available, small-molecule type I IFN receptor agonist that directly transduces the IFN signal cascade and stimulates antiviral gene expression. Like type I IFN, the small-molecule compound induces IFN-stimulated gene (ISG) expression for antiviral activity in vitro and in vivo in mice, and the ISG induction mechanism is attributed to a direct interaction between the compound and IFN-α receptor 2, a key molecule of IFN-signaling on the cell surface. Our study highlights the importance of an orally active IFN-like agent, both as a therapy for antiviral infections and as a potential IFN substitute.
BMY-28864, a water-soluble pradimicin derivative, had potent in vitro activity against a wide variety of fungi, including those associated with deep-seated mycosis; it inhibited the growth of standard strains and clinical isolates at concentrations of 12.5 ,ug/ml or less. At the MIC or higher concentrations, BMY-28864 was fungicidal for Candida albicans under both growing and nongrowing conditions. BMY-28864 expressed fungicidal activity only in the presence of Ca2+, and its activity was totally diminished when ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), a Ca2+ chelator, was added to the test medium. The effectiveness of intravenously administered BMY-28864 in vivo was examined and compared with that of amphotericin B in mouse models of fungal infections. Both normal and cyclophosphamide-treated immunosuppressed mice infected with C. albicans, Cryptococcus neoformans, or Asperi'lus fumigatus responded to therapy with BMY-28864 (50% protective doses of 17, 18, and 37 mg/kg of body weight in normal mice and of 32, 35, and 51 mg/kg in cyclophosphamide-treated mice, respectively). Lethal lung infections were also established with C. albicans or A. fumigatus in cyclophosphamide-treated mice. The 50% protective doses of BMY-28864 were 15 and 23 mg/kg per dose against C. albicans and A. fumigatus, respectively. The immunosuppression induced by intraperitoneal administration of 200 mg of cyclophosphamide per kg lasted for 5 days, and total recovery was observed by day 7.The rising incidence of systemic fungal infections in patients with suppressed immune systems brought about by the use of cytotoxic drugs, immunosuppressive therapy, or human immunodeficiency virus infection and the prolonged treatments that are necessary in these patients have highlighted the shortcomings of existing antifungal therapies. Amphotericin B remains the drug of choice for life-threatening fungal infections despite the relatively high degree of toxicity associated with its use, often a limiting factor in practice. Therefore, a need exists for fungicidal, broadspectrum, less-toxic antifungal agents to supplement the list of currently available antifungal drugs.Pradimicin A is the original member of the pradimicins produced by Actinomadura hibisca P157-2 (ATCC 53557) (14,15,23,24). It possesses potent activity in vitro against a wide range of pathogenic fungi (16) and demonstrates in vivo efficacy against a large number of Candida albicans isolates (3). Although pradimicin A is relatively nontoxic, its limited solubility in aqueous media at physiological pHs posed difficulties in further development. As part of the program aimed at identifying water-soluble derivatives, we embarked on microbial and chemical modification studies of pradimicin A (6, 7, 18, 20) and developed BMY-28864 (13) (Fig. 1).BMY-28864 was found to have broad and potent antifungal activity comparable to that of pradimicin A in vitro. It was water soluble (>40 mg/ml at pH 7.2) and well tolerated in mice; no acute lethal or apparent side effects...
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