Discovery of a Novel Class of Norovirus Inhibitors with High Barrier of Resistance

Abstract

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.

Identification of potential 3CLpro inhibitors-modulators for human norovirus infections: An advanced virtual screening approach

“…All age groups are susceptible to getting the HuNoV infection, however, children and the elderly are much more prone to get infection easily and also immunocompromised patients, and hence more likely to develop severe symptoms and so on priority wise are groups of interest for immunization [3,5]. Fecal-oral transmission, ingesting tainted food or drink, and personto-person contact are all common ways of spreading HuNoV infections [6]. HuNoV is thought to be accountable for ~699 million illnesses and ~219,000 fatalities annually in the world [7].…”

“…The NoV encompasses a genetically diverse group of nonenveloped positive-strand RNA viruses that infect many host species including humans and enterics in nature [6]. The genome of HuNoV is comprised of three open reading frames (ORFs) viz.…”