Novel class of norovirus inhibitors

Human noroviruses (HuNoVs) are the most common cause of viral gastroenteritis resulting in ~219,000 deaths annually. The current therapy consists merely of supportive supplementation with oral rehydration salts (ORS). There are still no antivirals or vaccines to treat and/or prevent HuNoV infections. An efficacious anti- norovirus drug that could be used as a prophylactic or to treat HuNoV infections is urgently needed. A large-scale antiviral drug screening, which included ~1000 drug-like small molecules from our compound library, allowed to identify the compound 1 (figure 1). The 3-((3,5-dimethylphenyl)sulfonyl)-5-chloroindole-N-(phenylmethanol-4-yl)-2-carboxamide (1) showed a good activity against the MNV replication with an EC50 of 0.5 ± 0.1 μM. Starting from the derivate 1, we designed and synthesized a set of 10 analogs of which a compound 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) 1. Time-of-drug-addition studies revealed that analog 2 acts at a time point that coincides with the onset of viral RNA replication. Resistance development is a major obstacle in antiviral therapy, and almost all active antiviral agents have shown to select for resistance mutations. To assess whether resistant variants to compound 6 would easily arise, we passaged the virus passaged in the presence of compound 6 up to 30 consecutive times. After reverse engineering S131T and Y154F as single mutations into the MNV backbone, we did not find a markedly compound 6res phenotype 1. In this study, we present a class of novel norovirus inhibitors with a high barrier to resistance and in vitro antiviral activity. References 1 J. V. Dycke, M. Puxeddu, G. La Regina, E. Mastrangelo, D. Tarantino, J. Rymenants, J. Sebastiani, M. Nalli, J. Matthijnssens, J. Neyts, R. Silvestri, and J. Rocha-Pereira, Pharmaceuticals 14 (2021) art. no. 1006.