ABSTRACT
Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 A, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.
Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Neuraminidase/antagonists & inhibitors , Orthomyxoviridae/enzymology , Animals , Antiviral Agents/therapeutic use , Cell Line , Chromatography, Gel , Cytopathogenic Effect, Viral/drug effects , Dogs , Enzyme Inhibitors/therapeutic use , Guanidines , Indicators and Reagents , Kinetics , Lung/metabolism , Male , Mice , Microscopy, Electron , Orthomyxoviridae/drug effects , Orthomyxoviridae/growth & development , Orthomyxoviridae Infections/prevention & control , Pyrans , Rats , Rats, Sprague-Dawley , Sialic Acids/chemistry , Sialic Acids/pharmacology , Structure-Activity Relationship , Viral Plaque Assay , Virus Replication/drug effects , ZanamivirABSTRACT
A set of trimeric and tetrameric derivatives 6-11 of the influenza virus neuraminidase inhibitor zanamivir 1 have been synthesized by coupling a common monomeric zanamivir derivative 3 onto various multimeric carboxylic acid core groups. These discrete multimeric compounds are all significantly more antiviral than zanamivir and also show outstanding long-lasting protective activity when tested in mouse influenza infectivity experiments.
