Abstract
Dengue virus is an important human pathogen threating people, especially in tropical and sub-tropical regions. The viral genome has one open reading frame and encodes one polyprotein which can be processed into structural and nonstructural (NS) proteins. Four of the seven nonstructural proteins, NS2A, NS2B, NS4A and NS4B, are membrane proteins. Unlike NS3 or NS5, these proteins do not harbor any enzymatic activities, but they play important roles in viral replication through interactions with viral or host proteins to regulate important pathways and enzymatic activities. The location of these proteins on the cell membrane and the functional roles in viral replication make them important targets for antiviral development. Indeed, NS4B inhibitors exhibit antiviral activities in different assays. Structural studies of these proteins are hindered due to challenges in crystallization and the dynamic nature of these proteins. In this review, the function and membrane topologies of dengue nonstructural membrane proteins are presented. The roles of solution NMR spectroscopy in elucidating the structure and dynamics of these proteins are introduced. The success in the development of NS4B inhibitors proves that this class of proteins is an attractive target for antiviral development.
Highlights
Dengue virus (DENV) and other viruses such as Zika virus and West Nile virus are members of the Flaviviridae family
Some membrane bound nonstructural proteins are considered in drug discovery and quite a few potent brane bound nonstructural proteins are considered in drug discovery and quite a few poinhibitors of NS4B have been developed [44,45,46]
The charged residue in a transmembrane domain can play a role in transmembrane helix packing [62], which might occur within NS2A transmembrane helices or in other viral membrane proteins
Summary
Dengue virus (DENV) and other viruses such as Zika virus and West Nile virus are members of the Flaviviridae family. Despite progress made in dewhich makes it possible to develop potent inhibitors [16,34,35,36,37]. One of the challenges is the hydrophilic nature of the active sites, which hinders the development of hydrophobic small-molecule inhibitors [39,40]. Some membrane bound nonstructural proteins are considered in drug discovery and quite a few potent brane bound nonstructural proteins are considered in drug discovery and quite a few poinhibitors of NS4B have been developed [44,45,46]. The functions and brane topologies of dengue nonstructural membrane proteins are described. Understandfolding and dynamics of these proteins will be useful for developing potent viral inhibitors. One of theTopologies characteristics these viral proteins is that all proteins contain
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