New ganglioside analogs that inhibit influenze virus sialidase

Abstract

Synthetic thioglycoside-analogs of gangliosides such as Neu5Acα)2-S-6)Glcβ-(1-1)Ceramide (1) and the GM3 analog Neu5Acα(2-S-6)Galβ-(1–4)Glcβ(1-1)Ceramide (2), competitively inhibited GM3 hydrolysis by the sialidase of different subtypes of human and animal influenza viruses with an apparent K_i value of 2.8×10⁻⁶ and 1.5×10⁻⁵ M, respectively. The inhibitory activity of the ganglioside GM4 analog [Neu5Acα-(2-S-6)Galβ-(1-1)Ceramide (3)], in which the glucose of 1 was substituted by galactose, was lower than that of 1 (K_i =1.0×10⁻⁴ M). The thioglycoside-analogs (1, 2, 3) of the gangliosides were nonhydrolyzable substrates for influenza virus sialidase. The inhibitory activity of 1 to bacterial sialidases fromClostridium perfringens andArthrobacter ureafaciens was considerably lower than that to influenza virus sialidase, indicating that the structure of the active site in bacterial and influenza virus sialidase may be different and the analogs may be useful to determine the orientation of the substrate to the active site of sialidases, especially of influenza viruses.