Researchers at the Universities of Lethbridge and Calgary have reported a unique structure in the genome of the Hepatitis B virus (HBV), furthering the knowledge and understanding about how human proteins interact with the viral genome.
HBV is one of the leading causes of liver diseases and cancer. Despite the availability of effective vaccines, approximately 250 million individuals are chronically infected worldwide. According to the Canadian Liver Foundation, approximately 250,000 to 460,000 Canadians may be chronically infected with HBV. The current treatment regimen for HBV comprises drugs that suppress the virus but when treatment is stopped, the infection usually relapses owing to the presence of the covalently closed compact DNA (cccDNA) genome of HBV in infected patients.
The study is jointly led by Dr. Trushar Patel, a Canada Research Chair in RNA and Protein Biophysics at the U of L, and Dr. Carla Coffin from U of C (coordinating site of the Canadian Hepatitis B Network). The study, entitled Identification and characterization of a G-quadruplex structure in the pre-core promoter region of hepatitis B virus covalently closed circular DNA, is published in the prestigious Journal of Biological Chemistry (JBC).
The JBC article by co-first authors Dr. Vanessa Meier-Stephenson and Dr. Maulik Badmalia reports the presence of a unique fold in the virus genome which is critical for binding to a human protein called Sp1 that helps the virus proliferate. An earlier study published by the same group first reported a conserved Guanine-rich stretch in the HBV genome indicating that this region may be able to form the unique DNA fold known as a G-quadruplex (G4). This sequence is further important as it is known to interact with the human protein Sp1. The group also investigated where or how these G4 quadruplexes bind, using hepatitis B positive liver samples from patients. Finally, using HBV infected cell lines, the group found that the sequence has a considerable effect on the production of virus proteins. The article published in JBC identifies a novel strategy for combatting HBV infection by targeting the HBV cccDNA which hides in the infected cells.
With this newfound knowledge, the group plans to investigate and study novel compounds for combatting the HBV infection, including those that specifically affect the interaction of cccDNA and human proteins. They have developed and patented a class of compounds to do just this and many of these compounds are already showing promising results in cell culture assays. Further pre-clinical work is underway.
This work was supported by Alberta Innovates, the Canadian Network on Hepatitis C Fellowship, the Canada Foundation for Innovation and Diamond Light Source (UK).
The full JBC article can be found here.
