Hepatitis C Helicase Inhibitors
- Technology Benefits
- Multiple effects – Inhibits both the helicase and protease activities of HCV NS3 Broad Acting – Inhibit all HCV genotypes with similar potency Fewer potential side effects – No detectable toxicity in cell culture Compatible with other DAAs– Enhance the effects of telaprevir Combination Potential – Shows synergy in combination with other drugs on market
- Technology Application
- Hepatitis C in combination with hepatitis B, accounts for about 75% of all liver disease around the world.170-200 million people are infected with HCV worldwide with 3-5 million in the USA. Chronic HCVinfection develops in 70%–85% of HCV-infected persons. 60%–70% of chronically infected persons haveevidence of active liver disease. The global Hepatitis C virus market is attractive due to high levels of unmet need. The unmet need in themarket is approximately 70%, which equals about $3 billion. Some of this market availability is due to thelack of effective options for treatment as well as the lack of treatments with good efficacy and moderate safety profiles. Serious side effects still exist with a majority of the single and combination treatmentsused today. The global Hepatitis C market was worth approximately $4.4 billion in in 2009. It is expectedto reach $9.8 billion by 2016.
- Detailed Technology Description
- The invention consists of new direct acting antivirals (DAAs) that act against the Hepatitis C virus (HCV)replicon and inhibit the NS3 helicase activity. These DAAs are additionally unique compared to otherHCV helicase inhibitors because they are also capable of inhibiting HCV NS3 protease activity.
- Application No.
- Non-Confidential Summary
- *Abstract
-
HCV needs a functional helicase to replicate in cells. While helicases have been widely studied aspossible drug targets, progress has been slow compared to other viral enzymes because the most potentcompounds are non-specific, and inhibit normal healthy cellular processes. HCV is typically treated withvarious combinations of the nucleoside analog ribavirin combined with one of several recombinant humanalpha interferons. Though such treatments are effective, therapy is poorly tolerated, expensive, and notequally effective against all HCV genotypes. DAAs typically are small molecules that inhibit viralenzymes. DAAs are considered better HCV treatments because, unlike interferon and ribavirin, DAAsdirectly attack proteins that HCV synthesizes in human cells.
Two DAAs, telaprevir and boceprevir, were recently approved for use in HCV patients, both are proteaseinhibitors but neither alone eradicates HCV infection because HCV rapidly evolves to become resistant tothem. The protease inhibitors need to be administered with interferon and ribavirin, and as aconsequence many patients still poorly tolerate the new therapies. Therefore, new DAAs for HCV asdescribed here are needed that might be used with telaprevir, boceprevir or similar drugs to replaceinterferon and ribavirin in HCV therapy.
- *IP Issue Date
- None
- *IP Type
- Download
- *Principal Investigator
-
Name: Jeffrey Aube
Department:
Name: Brian Blagg
Department:
Name: Kevin Frankowski
Department:
Name: David Frick, Associate Professor
Department:
Name: Kelin Li
Department:
Name: Frank Schoenen
Department:
- *Publications
- Sweeney NL, Hanson AM, Mukherjee S, Ndjomou J, Geiss BJ, Steel JJ, Frankowski KJ, Li K, SchoenenFJ, Frick DN. ABenzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. CS InfectDis. 2015 Mar 13;1(3):140-148. Ndjomou J, Corby MJ, Sweeney NL, Hanson AM, Aydin C, Ali A, Schiffer CA, Li K, Frankowski KJ,Schoenen FJ, Frick DN. Simultaneously Targeting the NS3 Protease and Helicase Activities for MoreEffective Hepatitis C Virus Therapy. ACS Chem Biol. 2015 Aug 21;10(8):1887-96. Li K, Frankowski KJ, Hanson AM, Ndjomou J, Shanahan MA, Mukherjee S, Kolli R, Shadrick WR,Sweeney NL, Belon CA, Neuenswander B, Ferguson J, Aubé J, Schoenen FJ, Blagg BSJ, Frick DN.Hepatitis C Virus NS3 Helicase Inhibitor Discovery. Probe Reports from the NIH Molecular LibrariesProgram [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.2011 Dec 16. Sweeney NL, Shadrick WR, Mukherjee S, Li K, Frankowski KJ, Schoenen FJ, Frick DN. Primulinederivatives that mimic RNA to stimulate hepatitis C virus NS3 helicase-catalyzed ATP hydrolysis. J BiolChem. 2013 Jul 5;288(27):19949-57. Ndjomou J, Kolli R, Mukherjee S, Shadrick WR, Hanson AM, Sweeney NL, Bartczak D, Li K, FrankowskiKJ, Schoenen FJ, Frick DN. Fluorescent primuline derivatives inhibit hepatitis C virus NS3-catalyzed RNAunwinding, peptide hydrolysis and viral replicase formation. Antiviral Res. 2012 Nov;96(2):245-55. Li K, Frankowski KJ, Belon CA, Neuenswander B, Ndjomou J, Hanson AM, Shanahan MA, Schoenen FJ,Blagg BS, Aubé J, Frick DN. Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated fromthe yellow dyes thioflavine S and primuline. J Med Chem. 2012 Apr 12;55(7):3319-30.
- Country/Region
- USA
