Gastroenterology 143:213C222 [PubMed] [Google Scholar] 23

Gastroenterology 143:213C222 [PubMed] [Google Scholar] 23. ability of molecules to selectively increase the fluidity of cholesterol-rich membranes was subsequently Rabbit Polyclonal to MAP3K8 developed. One compound that emerged from the library screen, topotecan, is able to very potently inhibit the fusion of liposomes with cell culture-derived HCV (HCVcc). These results yield new insights into HCV infection and provide a platform for the identification of new HCV inhibitors. INTRODUCTION Hepatitis C virus (HCV) infects at least 130 million people worldwide and is the major cause of chronic liver disease. Infected patients are at risk of developing fibrosis, cirrhosis, and liver cancer (1C3). Although HCV was identified in 1989, advances in treatment have been augmented since the development of cell culture-grown HCV (HCVcc) in 2005 (4C6). No vaccine is available, and the current treatment for HCV infection involves a weekly injection of pegylated alpha interferon and a twice-daily weight-based dose of ribavirin for 24 to 48 weeks. This standard of care is plagued by a long duration, limited efficacy, and serious side effects (7). Although the recent addition of new direct-acting antivirals (DAAs) targeting HCV NS3-4A proteasetelaprevir and boceprevirto the anti-HCV therapeutic arsenal have improved the cure rates, they must be used in combination with interferon, as HCV has a remarkable ability to overcome a single DAA. Telaprevir and boceprevir only work in patients infected with genotype 1 HCV and are both not very effective in patients who did not respond to pegylated interferon-ribavirin therapy (8). In addition, both telaprevir and boceprevir appear to worsen the already problematic side effects of the standard therapy, such as rashes and anemia (9). Currently approved DAAs and most molecules in the pipeline are protease inhibitors, nucleoside inhibitors, nonnucleoside inhibitors, and NS5A inhibitors (10). A major obstacle in combating HCV is the low fidelity of the viral replication machinery, enabling the virus to quickly develop resistance (11). To date, ITX-5061 is the only inhibitor of HCV entry that has entered clinical testing. ITX-5061 blocks a postbinding step in the viral entry process by directly interacting with the entry factor scavenger receptor B1 (SR-B1) (12). New DAAs targeting entry steps critical to viral infection with additive potency when combined with existing DAAs and exhibiting low cytotoxicity are highly desirable. HCV is an enveloped, positive-sense RNA virus belonging to the family. The 9.6-kb viral genome encodes a single large polyprotein that is processed by viral and cellular proteases to produce Agrimol B the virion structural proteins (core and glycoproteins E1 and E2), P7, and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). HCV infection involves multiple steps. Viruses first attach to target cells via glycosaminoglycans and low-density lipoprotein (LDL) receptors. After recruitment to the membrane, HCV binds sequentially to entry factors involving SR-B1, the tetraspanin CD81, the Niemann-Pick C1-like 1 (NPC1L1) cholesterol (Cho) uptake receptor, and proteins of tight junctions, i.e., CLDN1 and OCLD (13). HCV then enters cells at the tight junction via clathrin-mediated endocytosis and fuses with the host membrane in the late endosome. Progress in defining the molecular mechanism of HCV entry raises the opportunity to exploit new viral and host targets for therapeutic intervention. Entry inhibitors have the potential to limit the expansion of the infected cell reservoir, prevent reinfection after liver transplantation, and complement the many Agrimol B protease and polymerase inhibitors currently under development. Although the discovery of drugs targeting the entry stage is still in its infancy, antibodies against SR-B1 (14), CD81 (15), and CLDN1 (16), as well as a number of small-molecule inhibitors, have recently been developed and are able to effectively block HCV entry (17C24). Phenothiazines are a group of nitrogen- and sulfur-containing tricyclic compounds that were first synthesized by Bernthsen in 1883. Phenothiazines with dialkylaminoalkyl groups and small groups substituted at positions 10 and 2, respectively, were found to interact with the dopamine receptors and Agrimol B have exhibited valuable activities, such as neuroleptic, antiemetic, antihistaminic, antipruritic, analgesic, and anthelmintic activities (25). To date, more than 100 phenothiazines have been used in clinics to treat psychotic disorders, and over 5,000 phenothiazine derivatives have been synthesized. Other receptors that can be modulated by phenothiazines include histamine H1, adrenergic 1 and 2, muscarinic (cholinergic), and serotonergic receptors (25). In addition to neurotransmitter receptors, phenothiazines have also been reported to bind to calmodulin and block its calcium signal-transduction activity, inhibit clathrin-coated pit formation, and activate rynodine receptors (26). Antiviral and antimicrobial activities have also been Agrimol B described for phenothiazines and related compounds (27). Our lab and others recently identified three phenothiazinesfluphenazine, trifluoperazine, and.