Recent Anti-Influenza Strategies in Multivalent Sialyloligosaccharides and Sialylmimetics Approaches

Abstract

Sialic acid-containing oligosaccharides expressed on the respiratory tract epithelial cell surface are involved in influenza virus infection in both virus attaching and detaching processes. Therefore, inhibition of sialic acid-binding processes provides rational anti-influenza strategies. Previous exploring efforts using monosaccharide sialic acid-bearing macromolecules provided proof of concept for multivalent hemagglutinin inhibition. However, the monosaccharide sialic acid cannot account for the molecular determinant of virus receptor-binding specificity in the context of the whole sialyloligosaccharide receptor. On the other hand, neuraminidase inhibition efforts using sialylmimetics have resulted into two antiinfluenza drugs, zanamivir and oseltamivir, which have been shown to reduce both the severity and duration of influenza illness. Nevertheless, the usage of monomeric sialylmimetics requires relatively large amounts of expensive compounds, which may also induce virus resistance and side effect. Therefore, it is critical to develop new antiinfluenza drugs and improve the current antiinfluenza drugs. This review highlights recent explorations of multivalent sialyloligosaccharides-based influenza virus adhesion inhibition strategy and multivalent sialylmimetics-based influenza virus detachment inhibition strategy for these efforts.

A Small Molecule Inhibits Virion Attachment to Heparan Sulfate- or Sialic Acid-Containing Glycans

“…9). Treatment with monomeric sialic acid only partially inhibited hemagglutination, as expected (24,25,(48)(49)(50), and not to the same extent as EGCG (Fig. 9).…”

“…For example, heparin and other sulfated polysaccharides and polysulfonated compounds inhibit the adsorption of viruses that bind to heparan sulfate moieties (21)(22)(23). Sialyl mimetics inhibit the adsorption of IAV and other viruses that bind sialic acid (24,25,(48)(49)(50). Such compounds act as receptor mimics, competing with cellular heparan sulfate or sialic acid moieties for virion binding.…”

Glycomimetics and Glycodendrimers as High Affinity Microbial Anti‐adhesins

“…For example, successful syntheses of such molecules have been obtained for cholera toxin, [22,23] shiga toxin, [24][25][26] or influenza virus. [27,28] In the present work, we will focus on the results recently obtained against two human pathogens: uropathogenic E. coli and P. aeruginosa.…”

Pandemic and seasonal influenza: therapeutic challenges

“…Extensive study of these compounds led to the development of NA inhibitors, which are monomeric sialylmimetics [42]. Further study of a number of new sialyloligosaccharides and sialylmimetics that inhibit virus attachment by the hemagglutinin (HA), or inhibit viral detachment through the activity of the NA, has led to the development of two new drugs.…”

“…Further study of a number of new sialyloligosaccharides and sialylmimetics that inhibit virus attachment by the hemagglutinin (HA), or inhibit viral detachment through the activity of the NA, has led to the development of two new drugs. One, multimeric zanamavir, is in the preclinical stages and the other, DAS181(Fludase), is in Phase I clinical trials [41,42]. Novel entry blocker proteins, such as the 20 amino-acid peptide derived from fibroblast growth factor 4 that blocks viral entry by binding to the HA and exhibits antiviral activity against influenza in tissue culture and in mice are also under investigation [43].…”