2015
DOI: 10.1021/jm5019934
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Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies

Abstract: Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of anti-norovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using it… Show more

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Cited by 49 publications
(133 citation statements)
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“…In addition to potentially higher stability to metabolic enzymes these inhibitors exhibit increased cellular permeability. Further studies should be anticipated that are directed at optimizing the design strategies and improving the pharmacokinetic properties and metabolic stability of HuNoV protease inhibitors using structural analysis and cell-based assays [7476]. Considering that the active-site residues are highly conserved between the HuNoV proteases in various genogroups and picornavirus proteases, there is a distinct possibility of designing broad-spectrum protease inhibitors as antivirals [77].…”
Section: Non-structural Proteins As Targetsmentioning
confidence: 99%
“…In addition to potentially higher stability to metabolic enzymes these inhibitors exhibit increased cellular permeability. Further studies should be anticipated that are directed at optimizing the design strategies and improving the pharmacokinetic properties and metabolic stability of HuNoV protease inhibitors using structural analysis and cell-based assays [7476]. Considering that the active-site residues are highly conserved between the HuNoV proteases in various genogroups and picornavirus proteases, there is a distinct possibility of designing broad-spectrum protease inhibitors as antivirals [77].…”
Section: Non-structural Proteins As Targetsmentioning
confidence: 99%
“…Cocrystal structures of NV 3CLpro with peptidyl inhibitors reveal a network of backbone hydrogen bonds involving Ala158, Ala160, Gln110 and His30, as well as two critical hydrogen bonds between His157 and Thr134 and the carbonyl oxygen of the P 1 Gln side chain [27,29,33]. The backbone hydrogen bonds mimic an antiparallel β-sheet and serve to correctly orient and position the inhibitor to the active site [3435].…”
Section: Resultsmentioning
confidence: 99%
“…The inhibitory activity of the synthesized compounds against NV 3CLpro and their anti-norovirus activity in a cell-based replicon system, were evaluated as described in the experimental section [33,47]. The determined IC 50 in enzyme assay, EC 50 against NV in the replicon harboring cells (HG23 cells) or murine norovirus (MNV) in RAW264.7 cells, and CC 50 values in HG23 cells are listed in Tables 1 and they are the average of at least two determinations.…”
Section: Resultsmentioning
confidence: 99%
“…Using a robust FRET-based assay [53] and a cell-based replicon system [18], an array of inhibitors of the protease displaying anti-norovirus activity have been reported, including peptidyl transition (TS) inhibitors (aldehydes, α-ketoamides, α-ketoheterocycles) [5458] or latent TS inhibitors [59], and TS mimics (α-hydroxyphosphonates) ( vide infra ) [60]. The availability of several high resolution X-ray crystal structures with bound ligands has been invaluable in using structure-guided approaches in the design of inhibitors of the enzyme [55,57,6165]. …”
Section: Drugs Against Known Targetsmentioning
confidence: 99%
“…Peptidyl inhibitors of 3CL pro have demonstrated efficacy in the murine model of norovirus infection and are currently in preclinical development [55]. The synthesis of peptidyl derivatives of general structure (I) (Figure 2A) can be readily accomplished as illustrated in Figure 2B and representative results are summarized in Tables 1–2.…”
Section: Drugs Against Known Targetsmentioning
confidence: 99%