Hepatitis C virus (HCV) chronically infects 2-3% of the global population, predisposing the patients to chronic liver diseases and liver cancer. To combat this major public health threat, a detailed understanding of the viral molecules will greatly facilitate vaccine and anti-viral drug design. The HCV envelope glycoproteins (Env), comprised of heterodimers of the E1 and E2 viral glycoproteins, are important for viral attachment and entry into host cells, and the assembly of infectious virus particles. The E1 and E2 glycoproteins are potential targets for pharmacological and immunological intervention. The goals of this application are to determine the high-resolution crystal structure of HCV envelope glycoproteins, and the functions of the glycoproteins at the amino acid level. The results will aid the rational design of anti-viral drugs and vaccines, and to understand the viral entry mechanism.
The specific aims are (i) to determine the high-resolution crystal structure of HCV E2 and E2:receptor complex; (ii) to study the roles of individual amino acid residues in protein functions by a shotgun mutagenesis approach; and (iii) to determine the high-resolution crystal structures of HCV E1 and E1E2 complex.

Public Health Relevance

Determination of the high resolution structures of the envelope glycoproteins E1 and E2 of hepatitis C virus (HCV) will provide extremely valuable information for understanding HCV biology, for structure-based drug and vaccine design against this human pathogen. A lack of highly pure and natively folded viral glycoproteins that will form high quality protein crystals has been a roadblock for this scientific endeavor. We had recently overcome this roadblock in crystallizing HCV E2 core domain and solving its X-ray structure, thus enabling this project and the field to investigate the structure and function of HCV envelope glycoproteins in unprecedented detail.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI123365-01
Application #
9084122
Study Section
Virology - A Study Section (VIRA)
Program Officer
Koshy, Rajen
Project Start
2016-02-15
Project End
2021-01-31
Budget Start
2016-02-15
Budget End
2017-01-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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