Neuraminidase (NA), a surface glycoprotein of influenza virus, is a potential target for design of antiinfluenza agents. The crystal structure of influenza virus neuraminidase showed that in the active site 11 residues are universally conserved among all strains known so far. Several potent inhibitors based on the carbohydrate compound 2-deoxy-2,3-didehydro-D-N-acetylneuraminic acid (DANA) have been shown to bind to the conserved active site and to reduce virus infection in animals when administered by nasal spray. Inhibitors of this type are, however, rapidly excreted from physiological systems and may not be effective in order to provide long-time protection. A new class of specific NA inhibitors, which are benzoic acid derivatives, has been designed on the basis of the three-dimensional structure of the NA-DANA complex and modeling of derivatives of 4-(acetylamino)benzoic acid in the NA active site. Intermediates were synthesized and were shown to moderately inhibit the NA activity and to bind to the NA active site as predicted. These rudimentary inhibitors, 4-(acetylamino)-3-hydroxy-5-nitrobenzoic acid, 4-(acetylamino)-3-hydroxy-5-aminobenzoic acid, and 4-(acetylamino)-3-aminobenzoic acid, and their X-ray structures in complexes with N2 (A/Tokyo/3/67) and B/Lee/40 neuraminidases have been analyzed. The coordinates of such inhibitors complexed with NA were used as the starting model for further design of more potent benzoic acid inhibitors. Because the active site residues of NA are invariant, the designed aromatic inhibitors have the potential to become an antiviral drug against all strains of influenza virus.

The present study examined the effects of paradoxical sleep (PS) deprivation on the oxidative stress parameters: lipid peroxidation, superoxide dismutase, glutathione peroxidase, and glutathione in brain regions: cerebral cortex, striatum, hippocampus, thalamus, hypothalamus, and brain stem of adult (8 months) and old (24 months) rats. PS deprivation (96 h) was performed by the classical flower pot technique. PS deprivation did not affect oxidative stress parameters in the striatum of both age groups; and the activity of glutathione peroxidase was not affected in any of the studied brain regions in both age groups. PS deprivation decreased the levels of glutathione only in the hippocampus, thalamus and hypothalamus; the magnitude of decrease was higher in the old than in the adult age group. PS deprivation increased the superoxide dismutase activity in the cerebral cortex and brain stem but reduced it in the hippocampus, thalamus and hypothalamus in both age groups. Increases in the activity were greater in adult animals than in old ones; the decline in the activity was greater in the hippocampus of old animals than in that of the adult ones. Lipid peroxidation was reduced by PS deprivation in the cerebral cortex and brain stem but was elevated in the hypothalamus and thalamus: the magnitude of alteration in the cerebral cortex, brain stem, hippocampus and hypothalamus was higher in adult animals than in old ones. The results showed that oxidative stress was not uniformly affected in all the brain regions. The cerebral cortex and brain stem showed a fall in oxidative stress after PS deprivation; the fall was greater in the adult than in the old animals. However, the oxidative stress was elevated in the hippocampus, thalamus and hypothalamus, and old animals were more severely affected than the adult ones.

Influenza virus sialidase is a surface enzyme that is essential for infection of the virus. The catalytic site is highly conserved among all known influenza variants, suggesting that this protein is a suitable target for drug intervention. The most potent known inhibitors are analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en), particularly the 4-guanidino derivative (4-guanidino-Neu5Ac2en). We utilized the benzene ring of 4-(N-acetylamino)benzoic acids as a cyclic template to substitute for the dihydropyran ring of Neu5Ac2en. In this study several 3-(N-acylamino) derivatives were prepared as potential replacements for the glycerol side chain of Neu5Ac2en, and some were found to interact with the same binding subsite of sialidase. Of greater significance was the observation that the 3-guanidinobenzoic acid derivative (equivalent to the 4-guanidino grouping of 4-guanidino-Neu5Ac2en), the most potent benzoic acid inhibitor of influenza sialidase thus far identified (IC50 = 10 microM), occupied the glycerol-binding subsite on sialidase as opposed to the guanidino-binding subsite. This benzoic acid derivative thus provides a new compound that interacts in a novel manner with the catalytic site of influenza sialidase.

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