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From Molecules to Medicines pp 121–138Cite as

Progress on New Hepatitis C Virus Targets: NS2 and NS5A

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Abstract

Hepatitis C virus (HCV) is a major global health problem, affecting about 170 million people worldwide. Chronic infection can lead to cirrhosis and liver cancer. The replication machine of HCV is a multi-subunit membrane associated complex, consisting of nonstructural proteins (NS2-5B), which replicate the viral RNA genome. The structures of NS5A and NS2 were recently determined. NS5A is an essential replicase component that also modulates numerous cellular processes ranging from innate immunity to cell growth and survival. The structure reveals a novel protein fold, a new zinc coordination motif, a disulfide bond and a dimer interface. Analysis of molecular surfaces suggests the location of the membrane interaction surface of NS5A, as well as hypothetical protein and RNA binding sites. NS2 is one of two virally encoded proteases that are required for processing the viral polyprotein into the mature nonstructural proteins. NS2 is a dimeric cysteine protease with two composite active sites. For each active site, the catalytic histidine and glutamate residues are contributed by one monomer and the nucleophilic cysteine by the other. The C-terminal residues remain coordinated in the two active sites, predicting an inactive post-cleavage form. The structure also reveals possible sites of membrane interaction, a rare cis-proline residue, and highly conserved dimer contacts. The novel features of both structures have changed the current view of HCV polyprotein replication and present new opportunities for antiviral drug design.

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Author information

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Center for Advanced Biotechnology and Medicine, Rutgers University, NJ, USA

    Joseph Marcotrigiano

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  1. Joseph Marcotrigiano
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Editors and Affiliations

  1. Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel

    Joel L. Sussman

  2. Department of Chemical Sciences, University of Padova, Italy

    Paola Spadon

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Marcotrigiano, J. (2009). Progress on New Hepatitis C Virus Targets: NS2 and NS5A. In: Sussman, J.L., Spadon, P. (eds) From Molecules to Medicines. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2339-1_8

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