Influenza hemagglutinin inhibitors

The influenza virus inhibitors, zanamivir, and oseltamivir, act outside the cell after virus particles have been formed. The dtugs have been designed to fit into the active site of the viral envelope enzyme neuraminidase, which is required to cleave sialic acid off the surface of the producing cells. When its activity is blocked, new virus particles stay attached to the cell surface through binding of the virus protein hemagglutinin to sialic acid and are prevented from spreading to other cells. 

N. Nishigori, Y. Suzuki, O. Kanie, C.-H. Wong, A lysoganglioside poly-L-glutamic acid conjugate as a picomolar inhibitor of influenza hemagglutinin, Angew. Chem., Int. 

Zanamivir (Relenza) is a neuraminidase inhibitor with activity against influenza A and B strains. Like oseltamivir, zanamivir is a reversible competitive antagonist of viral neuraminidase. It inhibits the release of progeny virus, causes viral aggregation at the cell surface, and impairs viral movement through respiratory secretions. Resistant variants with hemagglutinin and/or neuraminidase mutations have been produced in vivo however, clinical resistance to zanamivir is quite rare at present. 

The latter approach has been followed in our laboratory. For instance, in studies related to the synthesis of potent multivalent sialoside inhibitors of influenza virus hemagglutinin [34], it became of interest to evaluate the immunogenicity of neoglycoproteins containing sialosides as sole immunodominant hapten. To this end, acetochloroneuraminic acid (1) was transformed into allyl glycoside 2 (Scheme 1) which upon reductive ozonolysis afforded aldehyde 3 in excellent overall yields [35], Reductive amination of 3 to bovine serum albumin (BSA) and tetanus toxoid provided immunogenic vaccines from which specific rabbit IgG anti-sialic acid antibodies were obtained [36]. In order... 

Roy and coworkers have designed inhibitors of influenza virus hemagglutinin based on several different dendrimer backbones [109,110]. Using solid phase syntheses, they generated sialic acid-displaying dendrimers based on a poly-L-lysine core structure (O Fig. 17) as ligands for influenza virus hemagglutinin. These dendrimers, which bear 2, 4, 8, or 16 pendant sialic... 

In another example of liposome usage, a multivalent display of a C-3-modified sialoside on liposomes has been shown to inhibit influenza virus replication [124]. Hemagglutinin and sialidase are both involved in both glycoproteins, are involved in attachment and detachment of viral particles on the host cell through recognition of sialyl residues. In this case, the C-3-modified sialoside liposome seems to be such a successful inhibitor of viral replication because it successfully targets two different enz)mes that act on multivalent carbohydrate displays. 

Figure 24 Sabesan s heptasaccharide influenza virus hemagglutinin (HA) inhibitors present bivalent sialic acid linked through disubstituted galactose core.

Neuraminidase inhibitors are analogs of sialic acid (7). They work by binding to the active, catalytic site of neuraminidase that protrudes from the surface of influenza viruses. Viral hemagglutinin binds to the intact sialic acid residues, which results in viral aggregation at the host cell surface and a reduction in the amount of virus that is released to infect other cells (13). 

Some early gIycodendrimers intended to make good inhibitors of influenza A virus hemagglutinin [49] were constructed following the divergent approach on a peptide core by solid phase methodology. Due to the lower symmetry of the core, the overall shape of these macromolecules was not as globular as claimed for Tomalia s Starburst dendrimers [51]. 

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