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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).
