title: Synthesis and evaluation of novel 3-C-alkylated-Neu5Ac2en derivatives as probes of influenza virus sialidase 150-loop flexibility.
abstract: Novel 3-C-alkylated-Neu5Ac2en derivatives have been designed to target the expanded active site cavity of influenza virus sialidases with an open 150-loop, currently seen in X-ray crystal structures of influenza A virus group-1 (N1, N4, N5, N8), but not group-2 (N2, N9), sialidases. The compounds show selectivity for inhibition of H5N1 and pdm09 H1N1 sialidases over an N2 sialidase, providing evidence of the relative 150-loop flexibility of these sialidases. In a complex with N8 sialidase, the C3 substituent of 3-phenylally-Neu5Ac2en occupies the 150-cavity while the central ring and the remaining substituents bind the active site as seen for the unsubstituted template. This new class of inhibitors, which can 'trap' the open 150-loop form of the sialidase, should prove useful as probes of 150-loop flexibility.
authors.affiliation: Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland 4222, Australia.
authors.forename: Santosh
authors.initials: S
authors.lastname: Rudrawar
authors.forename: Philip S
authors.initials: PS
authors.lastname: Kerry
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Rameix-Welti
authors.forename: Andrea
authors.initials: A
authors.lastname: Maggioni
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Dyason
authors.forename: Faith J
authors.initials: FJ
authors.lastname: Rose
authors.forename: Sylvie
authors.initials: S
authors.lastname: van der Werf
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Thomson
authors.forename: Nadia
authors.initials: N
authors.lastname: Naffakh
authors.forename: Rupert J M
authors.initials: RJ
authors.lastname: Russell
authors.forename: Mark
authors.initials: M
authors.lastname: von Itzstein
mesh_terms: D000478:Alkylation; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009980:Influenza A virus / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018583:Pliability / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C036137:2-deoxy-2,3-dehydro-N-acetylneuraminic acid; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid