Jenny Wilson

Recent strategies in the search for new anti-influenza therapies.

Influenza is a highly contagious, acute upper respiratory tract disease caused by influenza virus, a member of the Orthomyxoviridae family. The viral particles have two surface antigens, haemagglutinin and sialidase (neuraminidase) that extensively decorate the surface of the virus and have been implicated in viral attachment and fusion, and the release of virion progeny, respectively. The receptor for haemagglutinin is the terminal sialic acid residue of host cell surface sialyloligosaccharides, while sialidase catalyses the hydrolysis of terminal sialic acid residues from sialyloligosaccharides. Extensive crystallographic studies of both these proteins have revealed that the residues that interact with the sialic acid are strictly conserved. Therefore, these proteins make attractive targets for the design of drugs to halt the progression of the virus. Recent successful efforts in the search for new cures for influenza have led to the development of three clinically-useful anti-influenza drugs. All three are potent, selective inhibitors of influenza virus A and B sialidase. Strategies for the development of haemagglutinin inhibitors have also been devised.

Saturation transfer difference (STD) 1H‐NMR experiments and in silico docking experiments to probe the binding of N‐acetylneuraminic acid and derivatives to Vibrio cholerae sialidase

Saturation transfer difference (STD) 1H NMR experiments were used to probe the epitope binding characteristics of the sialidase [EC 3.2.1.18] from the bacterium Vibrio cholerae, the causative agent of cholera. Binding preferences were investigated for N‐acetylneuraminic acid (Neu5Ac, 1), the product of the sialidase catalytic reaction, for the known sialidase inhibitor 5‐acetamido‐2,6‐anhydro‐3,5‐dideoxy‐D‐glycero‐D‐galacto‐non‐2‐enoic acid (Neu5Ac2en, 2), and for the uronic acid‐based Neu5Ac2en mimetic iso‐propyl 2‐acetamido‐2,4‐dideoxy‐α‐L‐threo‐hex‐4‐enopyranosiduronic acid (3), in which the native glycerol side‐chain of Neu5Ac2en is replaced with an O‐iso‐propyl ether. The STD experiments provided evidence, supporting previous studies, that Neu5Ac (1) binds to the sialidase as the α‐anomer. Docking experiments using DOCK (version 4.0.1) revealed further information regarding the binding characteristics of the enzyme active site in complex with Neu5Ac2en (2) and the Neu5Ac2en mimetic (3), indicating an expected dominant interaction of the acetamide moiety with the protein. Proteins 2004.