Boceprevir: Difference between revisions
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==Mechanism of Action== | ==Mechanism of Action== | ||
Boceprevir is an inhibitor of the [[HCV]] NS3/4A protease that is necessary for the proteolytic cleavage of the [[HCV]] encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in [[HCV]]-infected host cells. In a biochemical assay, boceprevir inhibited the activity of recombinant [[HCV]] genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype. | |||
==References== | ==References== | ||
Revision as of 21:08, 2 January 2014
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Boceprevir (INN) is a protease inhibitor being studied as a treatment for hepatitis C.[1][2]It is being developed by Schering-Plough.[3] As of 2008, it is in phase II clinical trials.[3]The hepatitis C virus, often described as the “silent epidemic,” affects more than 170-180 million people around the world and as the most common blood borne infection worldwide it has become a serious global health crisis.2 [4] [5][6] It is currently the leading cause of chronic liver diseases which include cirrhosis, carcinoma and liver failure, and approximately 130 million patients with the disease are at high risk of developing one of these conditions.4 HCV is an enveloped virus with a 9.6 kb single-stranded RNA genome that serves as a template for viral replication that is translated into a polyprotein and cleaved by proteases to allow for viral assembly.5
Before the development of new, more successful drug therapies such as boceprevir, the leading standard treatment therapy included the combination of pegylated interferon and ribavirin over a prolonged period of 24 to 48 weeks.2 4 However, for the genotype 1 strain of the virus, which is the most prevalent, this regimen achieves the goal of sustained virologic response (SVR), in only about 50% of treated patients, and it tends to be poorly tolerated and requires injection.[7] [8] Boceprevir is part of a treatment regimen that has been found to easier to administer, less toxic, and overall more effective. It is expected that the development of boceprevir and other new treatment will significantly broaden the treatment options for infected individuals.4
The FDA has recently approved the drug boceprevir as a new and improved HCV therapy to be used in combination with peginterferon and ribavirin, the previous standard of treatment.[9] It is widely agreed that boceprevir seems to be a safe and effective treatment innovation. The drug will treat patients with hepatitis C genotype 1.1 Boceprevir, marketed as Victrelis by Merck, is the first HCV protease inhibitor to reach market and it expected to be a major advance in HCV treatment. Throughout its phases of study, boceprevir has been shown to provide more effective treatment than just the combination of peginterferon and ribavirin alone, and will offer a greater chance of cure than the previous standards of therapy.
Category
Antiviral
US Brand Names
VICTRELIS®
FDA Package Insert
Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages
Mechanism of Action
Boceprevir is an inhibitor of the HCV NS3/4A protease that is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells. In a biochemical assay, boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype.
References
- ↑ Degertekin B, Lok AS (2008). "Update on viral hepatitis: 2007". Curr. Opin. Gastroenterol. 24 (3): 306–11. doi:10.1097/MOG.0b013e3282f70285. PMID 18408458. Unknown parameter
|month=ignored (help) - ↑ Njoroge FG, Chen KX, Shih NY, Piwinski JJ (2008). "Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection". Acc. Chem. Res. 41 (1): 50–9. doi:10.1021/ar700109k. PMID 18193821. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 "Interim Results from Boceprevir Phase II Study in Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL - Forbes.com" (Press release). Forbes.com. Retrieved 2008-05-19.
- ↑ Susser, Simone, Christoph Welsch, Yalan Wang, Markus Zettler, Franciso S. Domingues, Ursula Karey, Eric Hughes, Robert Ralston, Xiao Tong, Eva Herrmann, Stefan Zeuzem, and Christoph Sarrazin. "Characterization of Resistance to the Protease Inhibitor Boceprevir in Hepatitis C Virus–infected Patients." Hepatology 50.6 (2009): 1709-718.
- ↑ Asselah, Tarik, and Patrick Marcellin. "New Direct-acting Antivirals' Combination for the Treatment of Chronic Hepatitis C." Liver International 31.S1 (2011): 68-22.
- ↑ Kwo, Paul Y., and Rakesh Vinayek. "The Therapeutic Approaches for Hepatitis C Virus: Protease Inhibitors and Polymerase Inhibitors." Gut and Liver 5.4 (2011): 406-17.
- ↑ DeNoon, Daniel J. "Boceprevir Boosts Hepatitis C Treatment Success." WebMD. WebMD Health News, 9 Aug. 2010. Web. <http://www.webmd.com/hepatitis/news/20100809/boceprevir-ups-hepatitis-c-treatment-success>.
- ↑ Flint, Mike, Stanley Mullen, Anne M. Deatly, Wei Chen, Lynn Z. Miller, Robert Ralston, Colin Broom, Emilio A. Emini, and Anita Y. M. Howe. "Selection and Characterization of Hepaitis C Virus Replicons Dually Resistant to the Polymerase and Protease Inhibitors HCV-769 and Boceprevir." Antimicrobial Agents and Chemotherapy 53.2 (2009): 401-11.
- ↑ Walker, Emily P. "Boceprevir Wins FDA Approval to Treat Hepatitis C." MedPage Today. N.p., 13 May 2011. Web.<http://www.medpagetoday.com/InfectiousDisease/Hepatitis/26469>.