New hepatitis C antiviral drugs

5 March 2009

chlorocebus-pygerythrusNearly 3% of the world’s population – about 175,000,000 individuals – are infected with hepatitis C virus (HCV), and 3-4 million new infections are added each year. A high percentage of these become life long, chronic infections, which may lead to cirrhosis, hepatocellular carcinoma, and death. No vaccine is available, and the only antiviral treatment, pegylated interferon plus ribavirin, is often ineffective and has adverse side effects. The extent and severity of hepatitis C has stimulated the development of many new antiviral compounds, including protease and polymerase inhibitors. Perhaps one of the most unusual treatments being considered is one that directly targets a small RNA, known as a microRNA (miRNA), that is abundant in the liver.

Micro RNAs are single-stranded RNA molecules 21-23 nucleotides long which regulate the expression of about 30% of all mammalian protein-coding genes. They act by binding to the 3′-non coding region of mRNAs which leads to degradation of the mRNA or inhibition of translation. When miRNAs were first discovered, many virologists searched for target sequences in viral genomes to discover new ways to inhibit viral replication. A binding site for a liver-specific miRNA, called miR-122, was found in the RNA genome of HCV. However the target site for miR-122 was found in the 5′-noncoding region of the mRNA, not in the 3′-end. To the investigators’ surprise, binding of miR-122 to the HCV RNA stimulated viral replication. HCV replication in cells lacking miR-122 is significantly reduced compared with cells that produce miR-122.

The requirement of miR-122 for HCV replication suggested that this miRNA could be a target for therapeutic intervention. One approach has been the use of antagomirs, which are small synthetic RNAs that are complementary to the miRNA target. By binding to the miRNA, antagomirs block their ability to bind the target sequence and inhibit their function. An antagomir to miR-122 was found to impair HCV replication in cultured liver cells. Last year, a phase I clinical trial of an miR-122 antagomir was initiated in humans.

An important question is whether inhibition of miR-122 influences the expression of cellular genes which might lead to adverse side effects. If the antagomir is ever licensed, it will have another benefit besides inhibiting HCV replication: reduced cholesterol levels. miR-122 is believed to be involved in the regulation of cholesterol, fatty acid, and lipid metabolism, and African green monkeys who were administered the miR-122 antagomir had reduced plasma cholesterol.

C. L. Jopling, MinKyung Yi, Alissa M. Lancaster, Stanley M. Lemon, Peter Sarnow (2005). Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA Science, 309 (5740), 1577-1581 DOI: 10.1126/science.1113329

Jan Krützfeldt, Nikolaus Rajewsky, Ravi Braich, Kallanthottathil G. Rajeev, Thomas Tuschl, Muthiah Manoharan, Markus Stoffel (2005). Silencing of microRNAs in vivo with ‘antagomirs’ Nature, 438 (7068), 685-689 DOI: 10.1038/nature04303

Y SHAN, J ZHENG, R LAMBRECHT, H BONKOVSKY (2007). Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes Gastroenterology, 133 (4), 1166-1174 DOI: 10.1053/j.gastro.2007.08.002

Joacim Elmén, Morten Lindow, Sylvia Schütz, Matthew Lawrence, Andreas Petri, Susanna Obad, Marie Lindholm, Maj Hedtjärn, Henrik Frydenlund Hansen, Urs Berger, Steven Gullans, Phil Kearney, Peter Sarnow, Ellen Marie Straarup, Sakari Kauppinen (2008). LNA-mediated microRNA silencing in non-human primates Nature, 452 (7189), 896-899 DOI: 10.1038/nature06783

  • http://chem-bla-ics.blogspot.com/ Egon Willighagen

    Hi there, interesting blog!

    So, what's the chemical structure of miR-122 and its antagomir?

  • http://www.virology.ws profvrr

    miR-122 sequence/structure is here: http://bit.ly/BmBxY. The antagomir is the complementary sequence, modified chemically for stability. See this article for more details: http://bit.ly/gH7aJ.

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  • http://www.mullerhans.com/ Hans Muller

    A FORGOTTEN HEPATITIS SOURCE AND A PREVENTION

    A NEW Hepatitis Prevention Strategy. HOW SHARED TOOLS CAN STOP SPREADING MANICURE INFECTIONS.
    By: Hans Muller, University of Rhode Island MBA, engineer and Inventor. Advisor: Dr. Carlos Roberto Viana Milward de Andrade, M.D. – CRM 5251502-7, Work Medicine and Dermatologist. Rio de Janeiro, Brazil

    It is a Global Public Health Problem. 500 million people are already carrying one of the Hepatitis B, C, etc. viruses. Most do not know it. Millions will soon need expensive treatments and die due to missing alerts and options. U.S. veterans and certain city areas have expressive number of infected people. Around 1.5 millions die every year and Governments and Health Authorities are lacking to start alerting campaigns to prevent these infections. Contaminations through shared manicure, pedicure, piercing, tattooing (ink), podiatry needles and instruments are frequent. Even shared razors, sniffing straws, crack pipes, injections and toothbrushes infect people. In less extend acne extractions and hair electrolysis also infect. The only method to right sterilize shared tools is by using an Autoclave but, only when the whole process is correctly done. It is a long and expensive process to do it right.

    In manicure and pedicure, when nails are only painted or cut not to close to the nails` bed, there is no contamination risk. But, millions do sophisticated nail cares, or treat sick nails and skin, where lacerations are frequent and micro-cuts or nicks can get infected through micro-particles of lymph, blood or serum exposures. In these cases, all sterilization means besides autoclaves, are not reliable, tools can infect like in Medical or Dental procedure. If so many ordinary infections are contaminating people, and these procedures involve cuts and nicks, how can someone avoid hepatitis, when tools are not right sterilized? Millions are being contaminated with bacteria, fungi and viruses. Disease like nail fungi (mycosis), warts, herpes, paronychias, piogenic granuloma, erysipelas, Hepatitis C, B, D, or G and other infections are rising. Once a person contracts one of these hepatitis viruses, it takes an average of 4 months for the first antibodies to appear in the blood and about 20 years for an illness to develop into a liver cirrhosis or cancer. This time factor makes a diagnosis difficult and is the main reason for so few prevention and research. The worst, the rising number of infected people is always more contaminating others, even through manicure tools. These viruses are hard to kill and survive normal sanitations. Some viruses were discovered in the last 20 years.

    Users need effective sanitary rules to prevent them from new contaminations. Infections are rising, and sterilization through the correct use of autoclaves must be the only acceptable method. Urgently new rules are necessary, users need more protection!

    The solutions to prevent these risks are: people should only use, their own strictly personal, or disposable or correctly autoclaved tools. But, for most users and nail technicians these 3 alternatives are too expensive and complicate, a real problem until now.

    Face to these limitations, an appropriate solution to prevent cross-contaminations, is to use a simple and inexpensive alternative that minimizes and can nullify health damages to individuals and communities. A solution that benefits all societies and nail technicians, is a tool of easy handling, hygienic, that facilitates finger, nail and cuticle care, and is of low cost. It is a small and complete kit that does nail care fast, perfectly, and in a safe manner. It is a device, when used as a personal tool avoids contracting third people`s diseases, finishing with this contamination risk. A tool when blades are worn-out, it is cheaper to repurchase a new one, than to resharpen any tool, than to buy a pricey separated instrument or to autoclave tools in use or kept in stock. It also offers the best, fastest and cheapest alternative to implant prevention of cross-infections. This tool needs a first class metallurgy to manufacture it. Advertisements focusing on prevention of illness will scale it’s sales in the worldwide market, compensating the high initial manufacturing costs. More details on this safe tool that makes saver nail cares, please visit the web-site: http://www.mullerhans.com

  • http://www.sunglassesuk.com/ Designer Sunglasses

    Nice article.. Here in the Philippines, About 3% of our population are suffering from hepatitis.. Hope our government will do something about this.. By the way.. Thanks for posting this..

  • DarcyKitchin

    I have been suffering of back and joints pain and muscular tension. I have been that my doctor prescribed and I feel a lot better now. But I was thinking about some natural remedies because I don't enjoy taking pills. Anodyne therapy seems to be exactly what I needed. There can't be anything harmful about light and the results sound promising.

  • rickybadgett

    im wondering when a new med will come out for hep c.i tride interferon and it did not work.can you tell me when this new drug will come out to save my life. rick

  • rickybadgett

    when will a new drug be readdy for people that took interferon and did not work for them.

  • rickybadgett

    im wondering when a new med will come out for hep c.i tride interferon and it did not work.can you tell me when this new drug will come out to save my life. rick

  • rickybadgett

    when will a new drug be readdy for people that took interferon and did not work for them.

  • wardeworth

    Treatment of hepatitis C shortly after a person living with HIV are infected, it has the best chance of success.Approximately two thirds of people living with HIV who have hepatitis C to obtain a therapeutic response is sustainable, but rather a response to treatment is only seen in about one third of HIV-positive patients with hepatitis Chronic C.

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  • OneChanceOneLife

    I think this is great news.If there is a new drug which can fight against hepatitis c and win I guess this should be launched immedialtely on large scale so everybody who suffers of this disease can treate him self.It is wonderful to know that there are people dedicating their life to a cause like this but I guess we need to protect ourselves too.We can;t expect sombody else to take care of us, of our health.

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    I really hope they’re able to get these new medicines into the market quickly to help as many as possible. 

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