Abstract
Nuclear magnetic resonance (NMR) spectroscopy plays important roles in structural biology and drug discovery, as it is a powerful tool to understand protein structures, dynamics, and ligand binding under physiological conditions. The protease of flaviviruses is an attractive target for developing antivirals because it is essential for the maturation of viral proteins. High-resolution structures of the proteases in the absence and presence of ligands/inhibitors were determined using X-ray crystallography, providing structural information for rational drug design. Structural studies suggest that proteases from Dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV) exist in open and closed conformations. Solution NMR studies showed that the closed conformation is predominant in solution and should be utilized in structure-based drug design. Here, we reviewed solution NMR studies of the proteases from these viruses. The accumulated studies demonstrated that NMR spectroscopy provides additional information to understand conformational changes of these proteases in the absence and presence of substrates/inhibitors. In addition, NMR spectroscopy can be used for identifying fragment hits that can be further developed into potent protease inhibitors.
Highlights
Flavivirus is a genus of viruses in the family Flaviviridae, and some members such as Dengue virus (DENV), West Nile virus (WNV), Zika virus (ZIKV), tick-borne encephalitis virus, and yellow fever virus are important human pathogens [1,2,3]
In the 1H–15N-heteronuclear single quantum coherence (HSQC) spectrum of free WNV protease, the cross-peaks corresponding to several residues at the active sites and from the C-terminus of the NS2B cofactor were not observed, which might be caused by the conformational exchanges of the C-terminal part of the cofactor region [53]
Nuclear magnetic resonance (NMR) spectroscopy could readily show the importance of P1-Arg residue for the activity of the inhibitor, as modifying its side chain abolished its interaction with WNV protease
Summary
Flavivirus is a genus of viruses in the family Flaviviridae, and some members such as Dengue virus (DENV), West Nile virus (WNV), Zika virus (ZIKV), tick-borne encephalitis virus, and yellow fever virus are important human pathogens [1,2,3]. The transmembrane domains of NS2B are critical for the membrane location of both NS2B and NS3 [17] These domains might be important for the membrane location of replication complex formed by the viral proteins. Structural studies of a target protein and its complex with a ligand/substrate provide useful information for rational drug design [23]. Accumulated studies showed that NMR, together with X-ray crystallography, is critical in the development of protease inhibitors
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