Over 150 million people worldwide are infected with the hepatitis C virus (HCV), which is an important cause of chronic liver disease. Current therapies are inadequate. Our long-term objective is to bring a new class of anti-HCV drugs to the clinic. We recently discovered and genetically validated a new target within the HCV non-structural protein NS4B, consisting of an arginine-rich-like motif that mediates specific binding to the 3'-terminus of the negative viral RNA strand. NS4B-RNA binding is essential for genome replication. A high- throughput microfluidic screen of a compound library identified clemizole hydrochloride as a potent inhibitor (IC50 24 nM) of this interaction, which also inhibits HCV replication in vitro at non-cytotoxic concentrations. Clemizole, a first generation HI antihistamine, was extensively used and extremely well tolerated in humans in the 1950s and 1960s without reported toxicities, but is not currently marketed (due to the availability of better antihistamines) and no drug master file is available. Preliminary data indicates that clemizole is highly concentrated in the liver (>100 fold plasma levels), demonstrates dramatic in vitro synergy with SCH503034, an HCV NS3 protease inhibitor in advanced clinical development, and presumably due to its unique bi-partitie target appears to result in dramatically less viral resistance than with agents against a single viral target. Finally, an overseas pilot study in 3 patients exhibited clearance of viremia following twice daily oral 100 mg clemizole for one month, without evidence of drug resistance. Together, the above exciting preliminary data suggest that clemizole (or a closely-related derivative) can represent both a paradigm-changing solution to a current large unmet medical need, as well as an important commercialization opportunity. We hypothesize that: 1) clemizole's dramatic synergy with SCH503034 extends to the general class of HCV protease inhibitors, and possibly other agents;2) clemizole-resistant mutants will retain their sensitivity to protease inhibitors and standard of care (interferon/ribavirin) agents (i.e there is no cross resistance);3) clemizole is highly concentrated in the liver over its entire dosing period;4) major metabolites of clemizole can be identified and synthesized for toxicity studies and determination of possible antiviral activity;5) while high intravenous bolus dosing can transiently prolong the QT-interval, normal oral dosing and extensive liver first- pass effect will prevent any significant QT prolongation;6) moreover, clemizole derivatives can be synthesized that are devoid of potential activity against the hERG and HI receptors while preserving anti-HCV activity. To test these hypotheses, we will perform synergy and cross-resistance studies, determine clemizole's full PK profile and major metabolites, and synthesize and evaluate the antiviral activity of selected metabolites and derivatives, in order to provide essential data for clemizole's pre-clinical package and eventual IND submission, as well as to identify a potential back-up (or second generation) lead molecule.
Hepatitis C virus (HCV) remains an important cause of worldwide liver disease for which current therapies are inadequate. We have discovered a novel target within the HCV NS4B protein and identified a small molecule- the first generation antihistamine clemizole--as a potent inhibitor of this target. Because clemizole was widely used in the past with remarkable safety and tolerability, and shows great promise in vitro and in vivo against HCV, we propose to further study this compound's potential for synergy with other anti-HCV agents, resistance profile, and major metabolites, as well as a selected group of clemizole derivatives, in order to both identify a back-up (or second generation) lead and to complete clemizole's pre-clinical package for IND submission, in the hope of developing an exciting new treatment option for patients.
|Gelman, Michael A; Glenn, Jeffrey S (2011) Mixing the right hepatitis C inhibitor cocktail. Trends Mol Med 17:34-46|
|Dvory-Sobol, Hadas; Pang, Philip S; Glenn, Jeffrey S (2010) The Future of HCV Therapy: NS4B as an Antiviral Target. Viruses 2:2481-92|