Peptide-β-lactam inhibitors of dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes.

@article{Drai2019PeptidelactamIO,
  title={Peptide-$\beta$-lactam inhibitors of dengue and West Nile virus NS2B-NS3 protease display two distinct binding modes.},
  author={Tonko Dra{\vz}i{\'c} and Sara Kopf and James Corridan and Mila M. Leuthold and Branimir Berto{\vs}a and Christian D P Klein},
  journal={Journal of medicinal chemistry},
  year={2019}
}
The β-lactam ring represents a valuable moiety that can induce covalent binding of an inhibitor to its target. In this study, we explored di- and tripeptides with β-lactam electrophilic warheads as inhibitors of dengue and West Nile virus NS2B-NS3 protease. Tripeptides with a (3S)-β-lactam moiety displayed highest activity, with IC50 and EC50 values in the lower micromolar range in biochemical and cellular assays. The activity against dengue protease was in general higher than against West Nile… 
View on PubMed
pubs.acs.org
12 Citations

12 Citations

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design
TLDR
The structures and dynamics of this protease in the absence and presence of inhibitors were explored to provide insights into the inhibitor design and the conformational changes of ZIKV protease and other proteases in the same family are discussed.
Identification and In Silico Binding Study of a Highly Potent DENV NS2B-NS3 Covalent Inhibitor.
TLDR
A potent NS2B-NS3 covalent inhibitor 23 was discovered through the chemical modification of a published covalENT inhibitor 1, followed by in vitro assay and comprehensive structure-activity relationship analysis throughcovalent docking and molecular dynamics simulation provides informative understanding of the binding modes of covalant inhibitors targeting NS2 B- NS3.
Discovery of potent benzoxaborole inhibitors against SARS-CoV-2 main and dengue virus proteases
Penicillin Derivatives Inhibit the SARS-CoV-2 Main Protease by Reaction with Its Nucleophilic Cysteine
TLDR
The synthesis of penicillin derivatives which are potent Mpro inhibitors are described and their mechanism of inhibition is investigated using mass spectrometric and crystallographic analyses to highlight the potential for inhibition of viral proteases employing nucleophilic catalysis by β-lactams and related acylating agents.
The spectrum between substrates and inhibitors: Pinpointing the binding mode of dengue protease ligands with modulated basicity and hydrophobicity.
Peptides targeting dengue viral nonstructural protein 1 inhibit dengue virus production
TLDR
Findings indicate the potential application of peptides targeting DENV NS1 as antiviral agents against dengue virus infection by specific peptides against DENV infection.
Conformational selection in the flaviviral NS2B-NS3 protease.
Facile Synthesis and In Vitro Activity of N-Substituted 1,2-Benzisothiazol-3(2H)-ones against Dengue Virus NS2BNS3 Protease
TLDR
Several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition and showed that two BITs could suppress DENV replication and virus infectivity.
Targeting the protease of West Nile virus.
TLDR
The viral protease NS2B–NS3 is among the most promising viral targets, making it a critical factor of viral replication, and despite strong efforts, no protease inhibitors have reached clinical trials yet.
Monocyclic beta–lactams for therapeutic uses: a patent overview (2010–2020)
TLDR
This review summarizes the relevant patent development on monocyclic beta-lactams in various therapeutic areas over the last 10 years and identifies some promising new clinical candidates in the field of neurodegenerative diseases and coagulation therapy.
...
...

References

SHOWING 1-10 OF 41 REFERENCES
Tripeptide inhibitors of dengue and West Nile virus NS2B-NS3 protease.
Discovery of Nanomolar Dengue and West Nile Virus Protease Inhibitors Containing a 4-Benzyloxyphenylglycine Residue.
The dengue virus (DENV) and West Nile Virus (WNV) NS2B-NS3 proteases are attractive targets for the development of dual-acting therapeutics against these arboviral pathogens. We present the synthesis…
Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease.
Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids.
Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors.
TLDR
The synthesis and in vitro characterization of potent peptidic inhibitors of dengue virus protease that incorporate phenylalanine and phenylglycine derivatives as arginine-mimicking groups with modulated basicity are reported.
Inhibitor Bound Dengue NS2B-NS3pro Reveals Multiple Dynamic Binding Modes.
TLDR
An unanticipated multibinding mode behavior of a representative of this class of inhibitors to dengue NS2B-NS3pro is demonstrated, illustrating the highly dynamic nature of both the covalently bound ligand and protease protein structure, and the need to consider these dynamics when designing future inhibitors in this class.
Binding of low molecular weight inhibitors promotes large conformational changes in the dengue virus NS2B-NS3 protease: fold analysis by pseudocontact shifts.
TLDR
A model of the protease built on the closed conformation of the related West Nile virus protease is a better template for rational drug design than available crystal structures, at least for positively charged inhibitors.
Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors.
C-terminal residue optimization and fragment merging: discovery of a potent Peptide-hybrid inhibitor of dengue protease.
TLDR
A two-step rational optimization led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 and the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengued protease.
A fluorescence quenching assay to discriminate between specific and nonspecific inhibitors of dengue virus protease.
...
...