Haemagglutinin inhibitors

R. Roy, D. Zanini, S. J. Meunier, and A. Romanowska, Solid phase synthesis of dendritic sialoside inhibitors of influenza A virus haemagglutinin, J. Chem. Soc. Chem. Commun. (1993) 1869-1872. 

Roy and coworkers 70 71] described the solid state preparation of the first four generations (e.g., 38) of the dendritic sialoside inhibitors of influenza A virus haemagglutinin... 

Scheme 4.13. Dendritic sialoside inhibitors of influenza A virus haemagglutinin constructed via the solid phase synthesis of a lysine-based superstructure.

The influenza virus is an RNA-(—)- virus and possesses its own RNA polymerase enzyme. The complete RNA genome codes for eight proteins - two structural (matrix) proteins M, and M2, haemagglutinin, and neuraminidase and four proteins involved in replication, three of which make up the polymerase enzyme. Substrates for this are the usual ribonucleosides and there has been some success with the use of nucleoside analogues as inhibitors of the enzyme. The drug ribavirin has been the most successful, although this has to be administered by aerosol. These days, its major use is for the treatment of infections caused by respiratory syncytial viruses (especially in children), since these can cause long-term morbidity. 

Since haemagglutinin is involved in the adhesion of influenza virus to epithelial cells, it is an attractive target for therapeutic intervention. The design and synthesis of potential inhibitors of haemagglutinin has been reviewed elsewhere [5, 7, 14, 17, 33, 34] and, apart from a brief discussion of the general approaches employed towards such anti-influenza agents, is outside the scope of this article. 

Influenza vims A has two surface glycoproteins that offer potential for the development of competitive multivalent sugar clusters featuring 5-A -acetyl neuraminic acid (Neu5Ac) units [35]. Haemagglutinin (HA) binds to sialic acid receptors and fuses the cell membranes of the vims and host and neuraminidase (NA), an enzyme, cleaves sialic acid residues and is involved in release of new vims by the host cell. Whilst small molecule inhibitors of NA, such as oseltamivir (Tamiflu) and zanamavir (Relenza), are now available, no therapy based on inhibition of binding of HA has reached the clinic. 

In related work polyacrylamides bearing sialic acids were made from the monomer (12) and were found to be inhibitors of the viral membrane protein haemagglutinin. Click and Knowles have produced compounds represented by (13) and related materials also for use in the study of binding to viruses. ... 

In food processing, the major objectives are sometimes achieved at the expense of some loss of recognised nutrients. However, in other cases, important nutrients may become available only after appropriate processing, since inhibitors or other interfering compounds may be destroyed or inactivated. Toxic factors can sometimes be destroyed by denaturation, as with enzymes, protease inhibitors and phyto-haemagglutinins. They can also be physically removed, for example by leaching, solvent extraction or solid classification methods, as in the removal of gossypol from cottonseed protein, or of phytate from cereals. 

ROMESTAND B, coRBiER F, ROCH p (2002), Protease inhibitors and haemagglutinins associated with resistance to the protozoan parasite, Perkinsus marinus, in the Pacific oyster, Crassostrea gigas. Parasitology, 125, 323-329. 

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