Structures and Dynamics of Dengue Virus Nonstructural Membrane Proteins

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.

Identification of new inhibitors of NS5 from dengue virus using saturation transfer difference (STD-NMR) and molecular docking studies

“…Recently, several repurposed drugs were evaluated against dengue virus, including sinefungin, ivermectin, lovastatin, prednisolone, modipafant, ketotifen, balapiravir, ribavirin, celgosivir, UV-4B, and chloroquine, but no signicant success has been reported yet. 23 Saturation transfer difference (STD-NMR) is a robust technique for the analysis of protein-ligand interactions, as well as for the identication of binding epitopes of a ligand. In this study, 75 compounds were evaluated against NS5 from our inhouse library, including US-FDA approved drugs and natural products, using saturation transfer difference (STD)-NMR spectroscopy.…”

“…Recently, several repurposed drugs were evaluated against dengue virus, including sinefungin, ivermectin, lovastatin, prednisolone, modipafant, ketotifen, balapiravir, ribavirin, celgosivir, UV-4B, and chloroquine, but no significant success has been reported yet. 23 …”

Identification of 6ω-cyclohexyl-2-(phenylamino carbonylmethylthio)pyrimidin-4(3H)-ones targeting the ZIKV NS5 RNA dependent RNA polymerase

“…In addition, the thumb domain has an initiation loop, which is primarily responsible for facilitating the initiation of ATP-specific RNAs and regulating the transition of subsequent elongation steps ( Bartholomeusz and Thompson, 1999 ). The finger domain is involved in the formation of the active site and NTP entry channel by controlling the de novo synthesis of RdRp ( Akiyama et al, 2021 ; Li and Kang, 2022 ). Finally, alanine substitutions have demonstrated that several N-pocket residues are critical for NS5 polymerase de novo activity as well as viral replication ( Ackermann and Padmanabhan, 2001 ; Malet et al, 2008 ).…”

Dengue virus NS4B protein as a target for developing antivirals

“…The genome contains one open reading frame and encodes a polyprotein that can be further processed into 10 proteins by both host and viral proteases. These viral proteins include three structural proteins namely capsid protein (C), premembrane protein (prM) and envelope protein (E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) ( Pierson and Kielian, 2013 ; Li and Kang, 2022 ). The structural proteins are the key components of viral particles.…”