捆绑SM社区

Improved drug evaluation enabled by studying virus defence mechanism

Researchers at 捆绑SM社区 have found a clue in developing new drug candidates to fight the hepatitis C virus (HCV) by identifying a defence mechanism in the virus similar to resistance found in HIV.

鈥淚f you understand the biochemical mechanisms of drug resistance, you may be able to develop drugs in the test tube that are more capable of doing their job in the clinic,鈥� says Dr. Matthias G枚tte, an associate professor in the Department of Microbiology & Immunology at 捆绑SM社区 and a recipient of a national career award from the Canadian Institutes of Health Research (CIHR). Antiviral therapies commonly employ inhibitors, compounds that block enzymes from reproducing the virus. The infection eventually subsides as a result. However, a defence mechanism previously identified in HIV works when the virus enzyme 鈥渆xcises鈥� inhibitors, removing them and allowing the virus to continue multiplying.

In their study, to be published in the August issue of the journal Antimicrobial Agents and Chemotherapy (AAC) but already available online, G枚tte and colleagues experimented with a promising class of inhibitors, called nucleoside analogues, to see whether hepatitis C uses a similar defence mechanism. They found that some of these inhibitors are efficiently excised, while others remain attached and block a crucial virus enzyme. Understanding how some nucleoside analogues counteract excision may enhance their function as drugs.

Since hepatitis C infection is a major cause of severe liver damage and liver cancer, further research is needed urgently, says G枚tte. There are an estimated 200 million hepatitis C-positive people worldwide. Approximately 1 per cent of Canadians are infected with the virus, some 250,000 people.

Several factors have held back the development of better treatment to fight HCV. People often carry the infection unknowingly because symptoms arise much later as compared with HIV. Tests for patient infection were only made comprehensive in the early nineties, and the tools required for advanced drug design were not available until recent years.

鈥淭reatment success depends largely on the strain of virus causing infection, and the current hepatitis C therapy is often thwarted by the most common strain. The success rate is much lower than seen in HIV drug treatment,鈥� says co-author Megan Powdrill, a graduate student who worked on the study. Dr. Claudia D鈥橝bramo, a former graduate student, and Dr. J茅r么me Deval, a former postdoctoral fellow, are also co-authors of the paper.

G枚tte鈥檚 group is taking lessons from HIV therapy and drug development to boost research on HCV. His group and colleagues from Gilead Sciences, a biopharmaceutical company in California, recently experimented with a drug called tenofovir. Unlike AZT, another major anti-HIV drug, tenofovir counteracts excision in HIV by forming an inactive complex with the enzyme. This paper will also be published in the August issue of AAC. 鈥淎lthough the formation of a similar complex with hepatitis C inhibitors is not evident,鈥� said G枚tte, 鈥渢his adds to our understanding of how viral resistance can be overcome.鈥�

This research was funded by the Cancer Research Society, the Canadian Institutes of Health Research (CIHR), the National Canadian Training Program in Hepatitis C (NCRTP-HepC) and the Fonds de la Recherche en Sant茅 du Qu茅bec (FRSQ).

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