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.

Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

“…Genogroups GI, GII, and GIV cause human acute gastroenteritis, with GII.4 variants being more prevalent and the cause of most norovirus outbreaks . There are currently no vaccines or small molecule therapeutics for the treatment or prophylaxis of norovirus infection . Targeting critical pathways in the norovirus life cycle holds promise for the discovery of norovirus therapeutics.…”

“…We have previously reported the structure‐guided design, synthesis and evaluation of multiple series of inhibitors of NV 3CLpro, including demonstration of efficacy in a mouse model of the disease using a dipeptidyl inhibitor . We have furthermore described the structure‐guided design of oxadiazole and triazole‐based macrocyclic transition state aldehyde inhibitors of NV 3CLpro (Figure ), as well as pertinent biochemical, structural, and high‐field NMR studies .…”

“…currently no vaccines or small molecule therapeutics for the treatment or prophylaxis of norovirus infection. [12][13][14][15][16] Targeting critical pathways in the norovirus life cycle holds promise for the discovery of norovirus therapeutics.…”

“…24,25 We have previously reported the structure-guided design, synthesis and evaluation of multiple series of inhibitors of NV 3CLpro, including demonstration of efficacy in a mouse model of the disease using a dipeptidyl inhibitor. 12,13,18 We have furthermore described the structure-guided design of oxadiazole and triazole-based macrocyclic transition state aldehyde inhibitors of NV 3CLpro ( Figure 2), as well as pertinent biochemical, structural, and high-field NMR studies. 27,28 In an attempt to gain insight and understanding into the nature of the interaction of macrocyclic inhibitors with NV 3CLpro, as well as delineate the structural elements of the inhibitors responsible for the observed potency and cellular permeability, we have determined additional high resolution X-ray structures of NV 3CLpro with triazole-based macrocyclic transition state aldehyde inhibitors.…”

Norovirus Infection (Systematic Review)

“…В качестве терапевтического потенциала для лечения норовирусного ОГЭ рассматриваются вирус-специфические моноклональные антитела [65]. В настоящее время также находятся в разработке ингибиторы протеаз вируса [66].…”