Eiger HCV NS4B Inhibitor Exhibits Synergy with Experimental HCV Protease Inhibitors

Question

“SUMMARY: The investigational hepatitis C virus (HCV) NS4B inhibitor clemizole demonstrated synergistic antiviral activity with the HCV protease inhibitors telaprevir and boceprevir -- meaning the combined effect was greater than the added effects of the 2 drugs used separately -- without increased toxicity, according to a laboratory study published in the July 1, 2010 Journal of Infectious Diseases.
		
The study also found that clemizole showed an additive, rather than synergistic, effect when combined with interferon, ribavirin, or the HCV polymerase inhibitors valopicitabine and HCV-796 (both discontinued).

The study authors, led by Jeffrey Glenn from Stanford University, founder of Eiger BioPharmaceuticals (the company developing clemizole), concluded that "Inclusion of clemizole in future anti-HCV cocktails can represent an attractive paradigm for increasing current virologic response rates…"
(more at the article…)

http://www.hivandhepatitis.com/hep_c/news/2010/0709_2010_a.html

spectda · Accepted Answer

I remember reading this a bit ago and Jeffrey Glen's research. I tried to get an appointment with him at standford but they said he was mostly just doing research and not taking new patients. 


Article abstract
Nature Biotechnology 26, 1019 - 1027 (2008) 
Published online: 31 August 2008 | doi:10.1038/nbt.1490

Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis
Shirit Einav1,2,5, Doron Gerber3,5, Paul D Bryson2, Ella H Sklan2, Menashe Elazar2, Sebastian J Maerkl3,4, Jeffrey S Glenn2 & Stephen R Quake3

Abstract
More effective therapies are urgently needed against hepatitis C virus (HCV), a major cause of viral hepatitis. We used in vitro protein expression and microfluidic affinity analysis to study RNA binding by the HCV transmembrane protein NS4B, which plays an essential role in HCV RNA replication. We show that HCV NS4B binds RNA and that this binding is specific for the 3' terminus of the negative strand of the viral genome with a dissociation constant (Kd) of 3.4 nM. A high-throughput microfluidic screen of a compound library identified 18 compounds that substantially inhibited binding of RNA by NS4B. One of these compounds, clemizole hydrochloride, was found to inhibit HCV RNA replication in cell culture that was mediated by its suppression of NS4B's RNA binding, with little toxicity for the host cell. These results yield new insight into the HCV life cycle and provide a candidate compound for pharmaceutical development.

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Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR 3115A, 269 Campus Drive, Stanford, California 94305, USA.
Department of Bioengineering, Stanford University and Howard Hughes Medical Institute, Stanford, California 94305, USA.
Present address: School of Engineering, École Polytechnique Fédérale de Lausanne, Building BM 2111, Station 17, 1015 Lausanne, Switzerland.
These authors contributed equally to this work.
Correspondence to: Jeffrey S Glenn2 e-mail: jeffrey.***@****

Correspondence to: Stephen R Quake3 e-mail: ***@****

frijole · Answer

the combined effect was greater than the added effects of the 2 drugs used separately -- without increased toxicity

Now that is a nice statement.  It seems that adding Tel or Boc can be pretty grueling on top of SOC. Just keep on researching.  That is what I think

frijole

portann · Answer

Wow, I've never heard of clemizole being in the works until now. So if it even improves the odds with the promising trio combo, what odds could we be looking at? Are we headed to astronomical numbers or what?

But no extra toxicity? How do they know so fast?

Susan

Eiger HCV NS4B Inhibitor Exhibits Synergy with Experimental HCV Protease Inhibitors

Hey C test results

HCV Rna pcr qualitative test at 35 days accurate ?

How likely is a false positive HCV AB test?

HIV test window affected by HCV co-infection

Hey C test results

HCV Rna pcr qualitative test at 35 days accurate ?

How likely is a false positive HCV AB test?

HIV test window affected by HCV co-infection

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