Key result
Compound 6, a novel norovirus inhibitor, demonstrated potent in vitro antiviral activity against mouse norovirus (EC50 0.2 ± 0.1 µM) and human norovirus GI replicon with a high barrier to resistance.
Why the study?
Human noroviruses are the most common cause of viral gastroenteritis, but there are currently no antivirals or vaccines available to treat or prevent infection.
Effect estimate: EC50 0.2 ± 0.1 µM
A novel class of norovirus inhibitors, particularly compound 6, demonstrates potent in vitro antiviral activity against mouse and human norovirus models with a high barrier to resistance.
Potential lead from MNV screen identified; leaves open translation to HuNoV antivirals in vivo or clinic.
Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting in ~219,000 deaths annually and a societal cost of ~USD60 billion. There are no antivirals or vaccines available to treat and/or prevent HuNoV. In this study, we performed a large-scale phenotypical antiviral screening using the mouse norovirus (MNV), which included ~1000 drug-like small molecules from the Drug Design and Synthesis Centre (Sapienza University, Rome). Compound 3-((3,5-dimethylphenyl)sulfonyl)-5-chloroindole-N-(phenylmethanol-4-yl)-2.carboxamide (compound 1) was identified as an inhibitor of MNV replication with an EC50 of 0.5 ± 0.1 µM. A series of 10 analogs were synthesized of which compound 6 showed an improved potency/selectivity (EC50 0.2 ± 0.1 µM) against MNV; good activity was also observed against the HuNoV GI replicon (EC50 1.2 ± 0.6 µM). Time-of-drug-addition studies revealed that analog 6 acts at a time point that coincides with the onset of viral RNA replication. After six months of selective pressure, two compound 6res variants were independently selected, both harboring one mutation in VPg and three mutations in the RdRp. After reverse engineering S131T and Y154F as single mutations into the MNV backbone, we did not find a markedly compound 6res phenotype. In this study, we present a class of novel norovirus inhibitors with a high barrier to resistance and in vitro antiviral activity.
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Dycke et al. (2021) studied Norovirus infection. Compound 6 (norovirus inhibitor) was evaluated on Inhibition of mouse norovirus replication (EC50) (EC50 0.2 ± 0.1 µM). Compound 6, a novel norovirus inhibitor, demonstrated potent in vitro antiviral activity against mouse norovirus (EC50 0.2 ± 0.1 µM) and human norovirus GI replicon with a high barrier to resistance.
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