PUBLICATION
A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo
- Authors
- Van Dycke, J., Dai, W., Stylianidou, Z., Li, J., Cuvry, A., Roux, E., Li, B., Rymenants, J., Bervoets, L., de Witte, P., Liu, H., Neyts, J., Rocha-Pereira, J.
- ID
- ZDB-PUB-210929-23
- Date
- 2021
- Source
- Viruses 13(9): (Journal)
- Registered Authors
- de Witte, Peter
- Keywords
- Caliciviridae, antivirals, danio rerio, infection, small molecule
- MeSH Terms
-
- Animals
- Caliciviridae Infections/drug therapy*
- Caliciviridae Infections/virology
- Cell Line
- Cytopathogenic Effect, Viral/drug effects
- Drug Resistance, Viral
- Isoxazoles/pharmacology
- Microbial Sensitivity Tests
- Molecular Docking Simulation
- Mutation
- Norovirus/drug effects*
- Norovirus/enzymology
- Norovirus/genetics
- Norovirus/physiology
- Peptide Hydrolases/genetics
- Peptide Hydrolases/metabolism
- Phenylalanine/analogs & derivatives
- Phenylalanine/pharmacology
- Pyrrolidinones/pharmacology
- RNA, Viral/metabolism
- Replicon
- Small Molecule Libraries
- Valine/analogs & derivatives
- Valine/pharmacology
- Viral Protease Inhibitors/chemistry
- Viral Protease Inhibitors/pharmacokinetics
- Viral Protease Inhibitors/pharmacology*
- Virus Replication/drug effects
- Zebrafish/virology
- PubMed
- 34578432 Full text @ Viruses
Citation
Van Dycke, J., Dai, W., Stylianidou, Z., Li, J., Cuvry, A., Roux, E., Li, B., Rymenants, J., Bervoets, L., de Witte, P., Liu, H., Neyts, J., Rocha-Pereira, J. (2021) A Novel Class of Norovirus Inhibitors Targeting the Viral Protease with Potent Antiviral Activity In Vitro and In Vivo. Viruses. 13(9):.
Abstract
Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting annually in ~219,000 deaths and a societal cost of ~USD 60 billion, and no antivirals or vaccines are available. Here, we assess the anti-norovirus activity of new peptidomimetic aldehydes related to the protease inhibitor rupintrivir. The early hit compound 4 inhibited the replication of murine norovirus (MNV) and the HuNoV GI.1 replicon in vitro (EC50 ~1 µM) and swiftly cleared the HuNoV GI.1 replicon from the cells. Compound 4 still inhibits the proteolytic activity. We selected a resistant GI.1 replicon, with a mutation (I109V) in a highly conserved region of the viral protease, conferring a low yield of resistance against compound 4 and rupintrivir. After testing new derivatives, compound 10d was the most potent (EC50 nanomolar range). Molecular docking indicated that the aldehyde group of compounds 4 and 10d bind with Cys139 in the HuNoV 3CL protease by a covalent linkage. Finally, compound 10d inhibited the replication of HuNoV GII.4 in infected zebrafish larvae, and PK studies in mice showed an adequate profile.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping