Galactose-conjugates of the oseltamivir pharmacophore--new tools for the characterization of influenza virus neuraminidases.
We describe the synthesis of mimetics of the alpha2-3 and alpha2-6 sialogalactoside substrates of influenza neuraminidase which include the oseltamivir pharmacophore, and report the sub-nanomolar affinities for these novel neuraminidase inhibitors. The challenge of synthesizing a Phospha-Oseltamivir/Tamiphosphor monoester involving the secondary 3-hydroxy group of galactose required to mimic the alpha2-3 sialogalactoside has been overcome by palladium-promoted coupling of the oseltamivir-derived vinyl iodide with a protected galactose-3-phosphonate. The difference in binding of these two inhibitors to a given influenza neuraminidase should be a function of its alpha2-3/alpha2-6-selectivity, an important, but not yet fully understood factor in the adaptation of highly pathogenic avian influenza viruses to human hosts.
Carbain
Benoit
B
Department of Chemistry and Biochemistry, University of Sussex, Brighton, UK BN1 9QG.
Martin
Stephen R
SR
Collins
Patrick J
PJ
Hitchcock
Peter B
PB
Streicher
Hansjörg
H
D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D005690:Galactose / Q000737:chemistry*; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology*; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053139:Oseltamivir / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding
D004791:Enzyme Inhibitors; D053139:Oseltamivir; D009439:Neuraminidase; D005690:Galactose