In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors

Guo, Jingxu; Douangamath, A.; Song, Weixiao; Coker, Alun R.; Chan, A. W. Edith; Wood, Steve; Cooper, J.B.; Resnick, E.; London, Nir; Delft, F. von

doi:10.1016/j.yjsbx.2020.100031

Cited by 3 publications

(3 citation statements)

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“…Hence, it is neces sary to identify regions that are highly conserved across the different genogroups and are essential for protease activity as potential binding sites for the antivirals. Recently, a study using crystal-based fragment screening has identified 15 inhibitors targeting regions be sides the active site in Southampton protease [104]. The authors identified multiple frag ment-based inhibitors to the regions, including the active site, the RNA-binding site, and the central cavity in the crystallographic tetramer interface.…”

Section: Perspectives and Future Directionsmentioning

confidence: 99%

Norovirus Protease Structure and Antivirals Development

Zhao

Song

et al. 2021

Viruses

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Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is an excellent target for developing small-molecule inhibitors. The current strategy for developing HuNoV protease inhibitors is by targeting the enzyme’s active site and designing inhibitors that bind to the substrate-binding pockets located near the active site. However, subtle differential conformational flexibility in response to the different substrates in the polyprotein and structural differences in the active site and substrate-binding pockets across different genogroups, hamper the development of effective broad-spectrum inhibitors. A comparative analysis of the available HuNoV protease structures may provide valuable insight for identifying novel strategies for the design and development of such inhibitors. The goal of this review is to provide such analysis together with an overview of the current status of the design and development of HuNoV protease inhibitors.

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Section: Perspectives and Future Directionsmentioning

confidence: 99%

Norovirus Protease Structure and Antivirals Development

Zhao

Song

et al. 2021

Viruses

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“…The analysis of a MAP-I-bound GI protease provided valuable information about substrate recognition and binding groups and validated rational structure-aided peptide design for anti-protease drug development [16]. Many other examples of inhibitor-bound GI HuNoV protease structures have also been determined, such as those described in references [17][18][19], with 51 crystal structures of GI noroviruses with and without inhibitors bound currently in the Protein Data Bank (PDB). In contrast, there are only two crystal structures of GII.4 proteases available (PDB codes 6NIR and 6B6I) which are both apoenzymes.…”

Section: Introductionmentioning

confidence: 96%

Crystal Structure of Inhibitor-Bound GII.4 Sydney 2012 Norovirus 3C-Like Protease

Eruera,

McSweeney,

McKenzie-Goldsmith

et al. 2023

Viruses

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Norovirus is the leading cause of viral gastroenteritis worldwide, and there are no approved vaccines or therapeutic treatments for chronic or severe norovirus infections. The structural characterisation of the norovirus protease and drug development has predominantly focused upon GI.1 noroviruses, despite most global outbreaks being caused by GII.4 noroviruses. Here, we determined the crystal structures of the GII.4 Sydney 2012 ligand-free norovirus protease at 2.79 Å and at 1.83 Å with a covalently bound high-affinity (IC50 = 0.37 µM) protease inhibitor (NV-004). We show that the active sites of the ligand-free protease structure are present in both open and closed conformations, as determined by their Arg112 side chain orientation. A comparative analysis of the ligand-free and ligand-bound protease structures reveals significant structural differences in the active site cleft and substrate-binding pockets when an inhibitor is covalently bound. We also report a second molecule of NV-004 non-covalently bound within the S4 substrate binding pocket via hydrophobic contacts and a water-mediated hydrogen bond. These new insights can guide structure-aided drug design against the GII.4 genogroup of noroviruses.

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“…SV3CP plays a key role in the processing of a 200 kDa polyprotein encoded by ORF1, which is essential to viral replication, and lacks human homologues, making it an ideal target for diagnosis. 17 The specificity of our designed substrate was examined, and the protease detection limit was determined to be 28.0 nM. Finally, the plasmonic sensing system's performance was tested in relevant biological matrices and had a notable performance in external breath condensate, urine, and 1% fecal matter.…”

Section: Introductionmentioning

confidence: 99%