Link : http://www.ncbi.nlm.nih.gov/pubmed/22644022
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a central role in viral infection and persistence, and is the basis for viral rebound after the cessation of therapy, as well as the elusiveness of a cure even after extended treatment. Therefore there is an urgent need for the development of novel therapeutic agents that directly target cccDNA formation and maintenance. By employing an innovative cell-based cccDNA assay, in which secreted HBeAg is a cccDNA-dependent surrogate, we screened an in-house small molecule library consisting of 85,000 drug-like compounds. Two structurally related disubstituted-sulfonamides (DSS), termed CCC-0975 and CCC-0346, emerged and were confirmed as inhibitors of cccDNA production, with EC(50) values at low micromolar levels in cell culture. Further mechanistic studies demonstrated that DSS compound treatment neither directly inhibited HBV DNA replication in cell culture, nor reduced viral polymerase activity in the in vitro endogenous polymerase assay, but synchronously reduced the levels of HBV cccDNA and its putative precursor, deproteinized relaxed circular DNA (DP-rcDNA). However, DSS compounds did not promote the intracellular decay of HBV DP-rcDNA and cccDNA, suggesting that the compounds primarily interfere with rcDNA conversion into cccDNA. In addition, we demonstrated that CCC-0975 was able to reduce cccDNA biosynthesis in duck hepatitis B virus infected primary duck hepatocytes. To our knowledge, this effort is the first attempt at identifying small molecules that target cccDNA formation, and DSS compounds thus potentially serve as proof-of-concept drug candidates for development into therapeutics to eliminate cccDNA from chronic HBV infection.
Thanks for the reference. This research came out from The Hepatitis B Foundation. One of the authors, Professor Guo is presenting a paper at the coming ISVHLD Conference to be held in Shanghai in June on this very topic, I think. Also, Dr Andrew Vaillant from Replicor will also be talking about his REP9AC at the same conference.
Copyright 1994-2016 MedHelp International. All rights reserved.
MedHelp is a division of Aptus Health.
This site complies with the HONcode standard for trustworthy health information.
The Content on this Site is presented in a summary fashion, and is intended to be used for educational and entertainment purposes only. It is not intended to be and should not be interpreted as medical advice or a diagnosis of any health or fitness problem, condition or disease; or a recommendation for a specific test, doctor, care provider, procedure, treatment plan, product, or course of action. Med Help International, Inc. is not a medical or healthcare provider and your use of this Site does not create a doctor / patient relationship. We disclaim all responsibility for the professional qualifications and licensing of, and services provided by, any physician or other health providers posting on or otherwise referred to on this Site and/or any Third Party Site. Never disregard the medical advice of your physician or health professional, or delay in seeking such advice, because of something you read on this Site. We offer this Site AS IS and without any warranties. By using this Site you agree to the following Terms and Conditions. If you think you may have a medical emergency, call your physician or 911 immediately.