Background: HCV infections are a serious threat to public health. An important drug target is the NS3 protease, for which several inhibitors are in clinical trials. Because of the high mutation rate of the virus, resistance against any HCV-specific drug is likely to become a substantial problem. Structure-activity data for the major resistant variants are therefore needed to guide future designs of protease inhibitors.
Methods: The inhibitory potency of tripeptide NS3 protease inhibitors, with either a P2 proline or phenylglycine, in combination with different P3 and P1-P1' groups, was assessed in enzyme activity assays using the full-length NS3 protein with known resistance-conferring substitutions A156T or D168V. The results obtained from these variants were compared with the inhibition of the wild-type enzyme. Molecular modelling was used to rationalize the biochemical results.
Results: Inhibitors combining the P2 proline and P1 (1R,2S)-1-amino-2-vinylcyclopropyl-carboxylic acid (vinylACCA) lost much of their potency on the resistant variants. Exchange of the P2 proline for phenylglycine yielded inhibitors that were equipotent on the wild-type and on the A156T and D168V variants. The same result was obtained from the combination of either the P2 residue with a norvaline or an aromatic scaffold in the P1 position.
Conclusions: The combination of a substituted P2 proline and P1 vinylACCA appears to be the main problem behind the observed resistance. Molecular modelling suggests an enforced change in binding conformation for the P2 proline-based inhibitors, whereas the phenylglycine-based inhibitors retained their wild-type binding conformation in the substituted forms of the enzyme.
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http://dx.doi.org/10.3851/IMP1655 | DOI Listing |
Mol Biotechnol
December 2024
Unit of Scientific Research, Applied College, Qassim University, Buraydah, 52571, Saudi Arabia.
The Zika virus (ZIKV), an arbovirus within the Flavivirus genus, is associated with severe neurological complications, including Guillain-Barré syndrome in affected individuals and microcephaly in infants born to infected mothers. With no approved vaccines or antiviral treatments available, there is an urgent need for effective therapeutic options. This study aimed to identify new natural compounds with inhibitory potential against the NS2B-NS3 protease (PDB ID: 5LC0), an essential enzyme in viral replication.
View Article and Find Full Text PDFJ Virol
December 2024
Institute of Virology, Department for Pathobiology, University of Veterinary Medicine, Vienna, Austria.
Unlabelled: Classical swine fever virus (CSFV) is a member of the genus within the family . The enveloped particles contain a plus-stranded RNA genome encoding a single large polyprotein. The processing of this polyprotein undergoes dynamic changes throughout the infection cycle.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.
Japanese encephalitis virus (JEV) NS2B-NS3 is a protein complex composed of NS3 proteases and an NS2B co-factor. The N-terminal protease domain (180 residues) of NS3 (NS3(pro)) interacts directly with a central 40-amino acid hydrophilic domain of NS2B (NS2B(H)) to form an active serine protease. In this study, the recombinant NS2B(H)-NS3(pro) proteases were prepared in and used to compare the enzymatic activity between genotype I (GI) and III (GIII) NS2B-NS3 proteases.
View Article and Find Full Text PDFAntiviral Res
December 2024
Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, D-69120, Heidelberg, Germany. Electronic address:
The viral NS2B-NS3 protease is a promising drug target to combat dengue virus (DENV) and other emerging flaviviruses. The discovery of novel DENV protease inhibitors with antiviral efficacy is hampered by the low predictive power of biochemical assays. We herein present a comparative evaluation of biochemical DENV protease assay conditions and their benchmarking against antiviral efficacy and a protease-specific reporter gene assay.
View Article and Find Full Text PDFChem Biodivers
November 2024
Department of Chemistry, Govt. P. G. College, Guna, Jiwaji University, Gwalior, postCode/>473001, India.
A condensation reaction was carried out between 4-nitro-ortho-phenylenediamine and 5-bromosalicyaldehyde to synthesize a novel Schiff base ligand 2,2'-[(1E,1'E)-(4-nitro-1,2-phenylene) bis (azaneylylidene) bis (methaneylylidene)] bis (4-bromophenol) [NB] in the current investigation. This was followed by the synthesis of metallic complexes comprising the Co(II), Ni(II), Cu(II) and Zn(II) transition metal ions. A hexadentate environment encircling metal complexes was corroborated by the results of varied spectroscopic methods that were employed to unravel the structure of the ligand and metal complexes.
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