Antiviral targets of human noroviruses

Abstract

Human noroviruses are major causative agents of sporadic and epidemic gastroenteritis both in children and adults. Currently there are no licensed therapeutic intervention measures either in terms of vaccines or drugs available for these highly contagious human pathogens. Genetic and antigenic diversity of these viruses, rapid emergence of new strains, and their ability to infect a broad population by using polymorphic histo-blood group antigens for cell attachment, pose significant challenges for the development of effective antiviral agents. Despite these impediments, there is progress in the design and development of therapeutic agents. These include capsid-based candidate vaccines, and potential antivirals either in the form of glycomimetics or designer antibodies that block HBGA binding, as well as those that target essential non-structural proteins such as the viral protease and RNA-dependent RNA polymerase. In addition to these classical approaches, recent studies suggest the possibility of interferons and targeting host cell factors as viable approaches to counter norovirus infection. This review provides a brief overview of this progress.

Genetic characterization of norovirus GII.4 variants circulating in Canada using a metagenomic technique

“…Another study has also reported that these genes can tolerate few nucleotide changes [ 48 ]. This observation is not unexpected due to their critical functions in viral replication, viral protease and RdRP genes are highly conserved [ 40 , 49 ] and have been attractive targets for the design and development of antiviral strategies. Nucleotide diversity was also observed in regions of the p48, NTPase and VPg genes.…”

Synthesis and antiviral evaluation of novel peptidomimetics as norovirus protease inhibitors

“…Even though there is no therapeutic approved for the treatment of norovirus (NoV) infections, peptidomimetic inhibitors of the NoV protease (Figure 1) have emerged recently as a promising option. 1 Indeed, NoV 3C-like cysteine protease is essential to generate mature nonstructural proteins by cleavage of the viral polyprotein. Transition state inhibitors, such as compound 1 , 2 in which the peptidic moiety is selectively recognized by the 3CL protease while the electrophilic warhead reacts with Cys139 to form a covalent bond, can block the protease enzymatic activity (Figure 2).…”

Structural features of glycan recognition among viral pathogens

“…Closer examination of the HBGA binding site reveals that there are two subsites involved in HBGA binding. A conserved primary site (site 1), binding either the Gal residue in GI or the secretor-Fuc in GII, and a secondary evolving site (site 2) that is susceptible to sequence and structural alterations, allowing strain-specific HBGA binding [18,20,21] (Figure 2b, c). Site 2 in GII.4 variants identified post-2002 have evolved the ability to bind non-secretor Lewis HBGAs, and that might explain the prevalence of these variants [18].…”