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.

Public Health Relevance

Hepatitis C virus chronically infects 170 million people worldwide and is a leading cause of liver disease. A protective vaccine is not yet available and therapeutic options are limited. The structural and functional results of the p7 channel to be obtained in this research are of great utility to the biomedical community for developing more potent small molecules against HCV infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Koshy, Rajen
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Harvard Medical School
Schools of Medicine
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Costello, Deirdre A; Villareal, Valerie A; Yang, Priscilla L (2016) Desmosterol Increases Lipid Bilayer Fluidity during Hepatitis C Virus Infection. ACS Infect Dis 2:852-862
Zhao, Linlin; Wang, Shuqing; Du, Lingyu et al. (2016) Structural basis of interaction between the hepatitis C virus p7 channel and its blocker hexamethylene amiloride. Protein Cell 7:300-304
Dev, Jyoti; Br├╝schweiler, Sven; Ouyang, Bo et al. (2015) Transverse relaxation dispersion of the p7 membrane channel from hepatitis C virus reveals conformational breathing. J Biomol NMR 61:369-78
Kalita, Monoj Mon; Griffin, Stephen; Chou, James J et al. (2015) Genotype-specific differences in structural features of hepatitis C virus (HCV) p7 membrane protein. Biochim Biophys Acta 1848:1383-92