Therapeutics and Immunoprophylaxis Against Noroviruses and Rotaviruses: The Past, Present, and Future

Abstract

Background: Noroviruses and rotaviruses are important viral etiologies of severe gastroenteritis. Noroviruses are the primary cause of nonbacterial diarrheal outbreaks in humans, whilst rotaviruses are a major cause of childhood diarrhea. Although both enteric pathogens substantially impact human health and economies, there are no approved drugs against noroviruses and rotaviruses so far. On the other hand, whilst the currently licensed rotavirus vaccines have been successfully implemented in over 100 countries, the most advanced norovirus vaccine has recently completed phase-I and II trials.

Methods: We performed a structured search of bibliographic databases for peer-reviewed research literature on advances in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis.

Results: Technological advances coupled with a proper understanding of viral morphology and replication over the past decade has facilitated pioneering research on therapeutics and immunoprophylaxis against noroviruses and rotaviruses, with promising outcomes in human clinical trials of some of the drugs and vaccines. This review focuses on the various developments in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis, such as potential antiviral drug molecules, passive immunotherapies (oral human immunoglobulins, egg yolk and bovine colostral antibodies, llama-derived nanobodies, and antibodies expressed in probiotics, plants, rice grains and insect larvae), immune system modulators, probiotics, phytochemicals and other biological substances such as bovine milk proteins, therapeutic nanoparticles, hydrogels and viscogens, conventional viral vaccines (live and inactivated whole virus vaccines), and genetically engineered viral vaccines (reassortant viral particles, virus-like particles (VLPs) and other subunit recombinant vaccines including multi-valent viral vaccines, edible plant vaccines, and encapsulated viral particles).

Conclusions: This review provides important insights into the various approaches to therapeutics and immunoprophylaxis against noroviruses and rotaviruses.

Keywords: Gastroenteritis; antiviral molecules; norovirus; other therapeutic approaches; passive immunotherapy; rotavirus; vaccines..

Fig. (1)

The norovirus genomic RNA, subgenomic RNA, and structural (VP1 and VP2) and nonstructural (p48, NTPase, p22, VPg, 3CLpro and RdRp] viral proteins. The VPg protein covalently binds to the 5’- end of the viral genomic and subgenomic RNA, whilst the 3’- end of the viral RNA is polyadenylated. Anti-noroviral targets, including potential targets, have been shown with symbol. 1. Virus capsid (VP1)-host cell receptor binding blockers: carbohydrate analogs of fucose (citrates, glucomimetics), heparan sulfate analogs (Suramin), soluble histones, tannic acid, and HBGA-blocking monoclonal antibodies. 2. 3C-like cysteine protease (3CLpro) inhibitors: peptidyl transition state (TS) inhibitors, latent peptidyl TS inhibitors, peptidyl TS mimics, Macrocyclic peptide inhibitors, and Rupintrivir. 3. RNA-dependent RNA-polymerase inhibitors: nucleoside (Ribavirin, Favipiravir and 2'-C-methyl-cytidine) and non-nucleoside (Suramin and NF023) analogs. 4. Targeting viral RNA: Peptide-conjugated phosphorodiamidate morpholine oligomers (PMO), and siRNA. 5. Targeting VPg-host factors interactions: Hippuristanol. 6. Targeting viral RNA-interacting host factors: potential inhibitors of factors, such as La, PTB, DDX3, PCPB2, and hnRNPs. 7. Targeting other host factors/pathways crucial to virus replication, such as inhibitors of cellular deubiquitinases (WP1130 and 2-Cyano-3-Acrylamide Compound-6), molecular chaperone hsp90, and cholesterol pathways.

Fig. (2)

Replication of rotavirus in host cell. Potential anti-rotaviral targets have been shown with symbol. 1. Blocking virus attachment and entry into host cells: sialylmimetics, lactadherin-derived peptides, neoglycolipid receptor mimetics, and membrane-impermeant thiol/disulfide-blockers. 2. Inhibition of viral RNA and/or protein synthesis: genistein, phosphonoformic acid [foscarnet, PFA], ribavirin and other nucleoside analogs, 3-deazaguanine (3-DG), neomycin and other aminoglycosides, actinomycin D, mycophenolic acid, isoprinosine, viscogens (glycerol), and siRNA. 3. Inhibition of viroplasm formation: nitazoxanide. 4. Suppression of virus replication, and/or virus maturation through inhibition of host cell lipid metabolism pathways and/or homeostasis of lipid droplets (LD): bile acids and farnesoid X receptor (FXR) agonists, 5-(tetradecyloxy)-2-furoic acid (TOFA), triacsin C, isobutylmethylxanthine (IBMX) + isoproterenol, stilbenoids, lovastatin, and cyclooxygenase inhibitors. Lipogenesis and its role in rotavirus replication has been excellently reviewed by Lever and Desselberger, 2016 [169]. This image has been modified with permission from the original source: ViralZone www.expasy.org/viralzone, © SIB Swiss Institute of Bioinformatics [297]. RER, rough endoplasmic reticulum.