Bioorganic & Medicinal Chemistry 2006-02-01

The synthesis and biological evaluation of lactose-based sialylmimetics as inhibitors of rotaviral infection.

Angela Liakatos, Milton J Kiefel, Fiona Fleming, Barbara Coulson, Mark von Itzstein

Index: Bioorg. Med. Chem. 14 , 739-57, (2006)

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Abstract

Rotaviruses are the most significant cause of gastroenteritis in young children and are responsible for over 600,000 infant deaths annually. The rotaviral haemagglutinin protein (VP8*) of some strains has been implicated in early recognition and binding events of host cell-surface sialoglycoconjugates, and is therefore an attractive target for potential therapeutic intervention. Since N-acetylneuraminic acid alpha(2,3)-linked to galactose is believed to be the minimum binding epitope of rotavirus to host cells, we report here our development of an efficient and flexible synthetic route to a range of lactose-based sialylmimetics of alpha(2,3)-linked thiosialosides. These compounds were biologically evaluated as inhibitors of rotaviral infection using an in vitro neutralisation assay. The results suggest that these lactose-based sialylmimetics are not inhibitors of the rhesus rotavirus strain; however, they do exhibit modest inhibition of the human (Wa) strain, presumably through inhibition of the rotaviral adhesion process.