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D. Lorne Tyrrell教授:拉米夫定治疗乙肝相关进展

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发布日期:2008-09-12 17:25 文章来源:第十次全国感染病学术会议组委会
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关键词: HBV 拉米夫定 进展 第十次 全国感染病学术会议   点击次数:

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The Development of Lamivudine for Hepatitis B Therapy:From the Farm to Big Pharma

University of Alberta, Edmonton, Alberta, Canada
D. Lorne Tyrrell


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Lorne Tyrrell教授解答问题

Hepatitis B virus (HBV) causes chronic infection in approximately 400 million people worldwide.HBV is responsible for more than one million deaths annually from cirrhosis or hepatocellular cancer.

In 1986, my laboratory adopted the primary duck hepatocyte culture system described by Summersand Mason (1) to screen for antivirals active against duck hepatitis B virus (DHBV). I collaborated with Dr. Morris Robins, a nucleoside chemist at the university of Alberta and later at Brigham Young University. We initially demonstrated that purine 2', 3' dideoxynucleosides  were much more potent than pyrimidine 2', 3' dideoxynucleosides (2, 3) against DHBV. This selectivity was based on binding of  2', 3' dideoxynucleoside 5' triphosphate to the viral polymerase to block the protein priming of the negative strand of DNA  synthesis (4). The purine 2', 3' dideoxynucleosides were also potent in vivo against DHBV. These antiviral compounds were  patented and this led to a research collaboration with Glaxo Canada on the development of antivirals for HBV.

Through this collaboration many small molecules were screened for antiviral activity against DHBV in the duck primary  hepatocyte culture system. Lamivudine (L-2', 3' dideoxy-3'-thiacytidine), was shown to have potent antiviral activity against  DHBV in duck hepatocytes and HBV in 2.2.1.5 cells expressing HBV (5). We demonstrated its activity against HBV in  chimpanzees  (6) and this led to the first clinical trial of lamivudine for the treatment of HBV in humans (7). Using site-specific  mutagenesis, we later demonstrated that single nucleotide changes in the YMDD motif of the viral polymerase produced  VDD
or YIDD mutants which had much higher IC50 values. On this basis, we predicted that YMDD mutants would be induced with  lamivudine monotherapy of HBV (8).

Fortunately, newer generations of antivirals active against HBV are less prone to induce resistance and can effectively treat  lamivudine-resistant mutants of HBV (9). With the prospect of long-term therapy of HBV with nucleoside analogues, safety of  prolonged therapy, and role of combination antiviral therapy remains to be clarified (9).

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