Function and mechanism of the HCV p7 channel and its therapeutic potential

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): This proposal aims to investigate the function and therapeutic potential of the viroporin protein, p7, of Hepatitis C virus (HCV) using a combination of structural and functional approaches. The p7 protein encoded by the HCV genome is required for viral replication; it has been shown to facilitate efficient assembly and release of infectious virions. In membrane, p7 forms a cation-selective channel. The structure of the p7 channel solved recently in our lab shows a novel architecture developed by the virus to conduct cations across the membrane. The structure also revealed channel elements that partially resemble those of known Ca2+/Mg2+ channels, which provide clues for further research to understand channel mechanism. Like most viroporins, the function of p7-mediated cation conduction during viral assemble and release remains elusive. The fact that p7 forms a well-defined channel structure suggests a role of ion permeability in these processes, and urges new investigations to better define this role. The p7 channel has also been pursued as an anti-HCV target because blocking the channel activity reduced production of infectious viral progeny. Several compounds have already been shown to inhibit channel activity, including the adamantane derivatives that also block the influenza M2 channel. These drug interactions could provide useful information for rational drug development, but how and where do these compounds act on the p7 channel are unknown. We propose to employ multidisciplinary approaches in biophysics, molecular virology, and medicinal chemistry to investigate the mechanism of cation conduction, the effect of channel activity in virus assembly and release, and the structural bases of channel inhibition by the known inhibitors. The knowledge to be gained from the proposed research may give rise to new opportunities for developing compounds for treating HCV infections.