Structure and functionality in flavivirus NS-proteins: Perspectives for drug design

Abstract

Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded RNA genome. Besides yellow fever virus, a landmark case in the history of virology, members of the Flavivirus genus, such as West Nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. Additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. Nevertheless, up to few years ago flaviviruses were considered low interest candidates for drug design. At the start of the European Union VIZIER Project, in 2004, just two crystal structures of protein domains from the flaviviral replication machinery were known. Such pioneering studies, however, indicated the flaviviral replication complex as a promising target for the development of antiviral compounds. Here we review structural and functional aspects emerging from the characterization of two main components (NS3 and NS5 proteins) of the flavivirus replication complex. Most of the reviewed results were achieved within the European Union VIZIER Project, and cover topics that span from viral genomics to structural biology and inhibition mechanisms. The ultimate aim of the reported approaches is to shed light on the design and development of antiviral drug leads.

Analysis of Ribonucleotide 5′-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays

“…By homology with other Flavivirus members, the catalytic region of the enzyme is located within the C-terminal portion of the NS5 protein. Additionally, the NS5 protein also contains methyltransferase activity in the N-terminal portion of the NS5 protein, which is involved in the capping of plus-strand genomic RNA (10)(11)(12). The overall architecture of the ZIKV RdRp most likely resembles the canonical right-hand conformation, consisting of fingers, palm, and thumb subdomains, that has been typical for all known polymerase structures and is similar to that reported for the RdRps of other members of the Flaviviridae family, including hepatitis C virus (HCV) and DFV.…”

A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target

“…Flaviviral NS3 proteins employ NS2B rather than NS4A as protease cofactor (see ref. 22 for a review). Compared to the hepaciviral HCV NS3/4A, the flaviviral NS3/2B proteins show a different respective arrangement of protease and helicase domains with the protease active site fully solvent exposed.…”

Antiviral Activity of Thiazolide Derivatives Against Dengue Virus in Huh-7 Cell Line

“…The functional inhibition of viral NS proteins is mainly based on the anti-flavivirus drug development (10,20). In fact, the NS3 protein is multifunctional enzyme, which has three important regions including serine protease, helicase, and a nucleotide triphosphatase (7,21).…”

“…The dengue virus, a member of the genus Flavivirus of the family Flaviviridae, is an arthropod-borne virus that includes four different serotypes (DENV1-4) (4,8,10). These viruses are enveloped and have a single-stranded positivesense RNA genome of approximately 11 kb (7).…”