Anti-norovirus therapeutics: a patent review (2010-2015)

ABSTRACT

Introduction: Human noroviruses are the primary causative agents of acute gastroenteritis and are a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. An improved understanding of norovirus biology, as well as the pathogenic mechanisms underlying the disease, has provided the impetus for a range of intense exploratory drug discovery efforts targeting viral and host factors.

Areas covered: An overview of norovirus inhibitors disclosed in the patent literature (2010-present) and Clinicaltrials.gov is presented. The review is further enriched and supplemented by recent literature reports.

Expert opinion: Seminal discoveries made in recent years, including a better understanding of the pathobiology and life cycle of norovirus, the identification and targeting of multiple viral and host factors, the advent of a replicon system and a small animal model for the preclinical evaluation of lead compounds, and the availability of high resolution X-ray crystal structures that can be utilized in structure-based drug design and lead optimization campaigns, collectively suggest that a small molecule therapeutic and prophylactic for norovirus infection is likely to emerge in the not too distant future.

KEYWORDS:

• Norovirus infection
• 3CL protease inhibitors
• RdRp inhibitors
• attachment and entry inhibitors
• host factors

Article highlights

• Acute nonbacterial gastroenteritis caused by noroviruses has a major impact on public health worldwide.

• No norovirus-specific therapeutic or vaccine is currently available.

• Drug discovery efforts in the norovirus field are handicapped by the lack of an ideal animal model and a human norovirus cell culture system.

• Most drug discovery efforts involve early preclinical studies and are focused on viral (entry blockers, 3CL protease, and RdRp inhibitors) and host factors (Hsp90 and deubiquitinase inhibitors).

• HTS using a cell-based replicon system may result in the identification of novel drug-like chemotypes.

• Evaluation of repurposed drugs may be a fruitful avenue of investigation.

• The availability of structural information and an increased understanding of the etiology of acute gastroenteritis are likely to accelerate drug discovery efforts.

This box summarizes key points contained in the article.

Financial and competing interests disclosure

The authors were supported by the National Institutes of Health under grant number R01AI109039. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.