Inhibition of sialidases from viral, bacterial and mammalian sources by analogues of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid modified at the C-4 position

Abstract

The inhibition of sialidase activity from influenza viruses A and B, parainfluenza 2 virus, Vibrio cholerae, Arthrobacter ureafaciens, Clostridium perfringens, and sheep liver by a range of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid analogues modified at the C-4 position has been studied. All substitutions tested resulted in a decrease in the degree of inhibition of the bacterial and mammalian sialidases. For sialidases from influenza viruses A and B, on the other hand, most of the substitutions tested either had no significant effect on binding or, in the case of the basic amino and guanidino substituents, resulted in significantly stronger inhibition. The results for parainfluenza 2 virus sialidase were mostly intermediate, in that inhibition was neither significantly increased nor decreased by most of the modifications. We conclude that only the influenza A and B sialidase active sites possess acid groups correctly positioned to participate in charge-charge interactions in the region of C-4 of bound substrate, and that the C-4 binding pockets of the bacterial and mammalian sialidases examined are considerably smaller than is observed for either the influenza virus or parainfluenza virus sialidases.

Influenza virus neuraminidase: Structure, antibodies, and inhibitors

“…The 4-substituted derivatives of NeuSAc2en described above show poor inhibitory activity when assayed against neuraminidase from paramyxoviruses, bacteria, or mammals (Table 1; Holzer et al, 1993;. Neu5Ac2en, however, has a Ki of approximately 1 pM against all enzymes, consistent with the existence of a similar enzyme-reaction mechanism in each case.…”

The Sialidases of Clostridium perfringens Type D Strain CN3718 Differ in Their Properties and Sensitivities to Inhibitors

“…Various inhibitors have been reported to reduce the activity of C. perfringens sialidases (27)(28)(29). However, most of those previous inhibitor studies did not specify which C. perfringens sialidase was used and none of them had compared the inhibitor sensitivity of all three C. perfringens sialidases in a side-by-side experiment.…”

Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections

“…3,4 This enzyme, essential for replication in vitro, 5 cleaves terminal sialic acid residues from glycoconjugates to allow the release of virus from infected cells, prevent the aggregation of virus, and possibly reduce viral inactivation by respiratory mucus. 6,7 Zanamivir inhibits a range of influenza A and B viruses in vitro.…”