Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen.
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.
Macdonald
Simon J F
SJ
GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom. simon.jf.macdonald@gsk.com
Watson
Keith G
KG
Cameron
Rachel
R
Chalmers
David K
DK
Demaine
Derek A
DA
Fenton
Rob J
RJ
Gower
David
D
Hamblin
J Nicole
JN
Hamilton
Stephanie
S
Hart
Graham J
GJ
Inglis
Graham G A
GG
Jin
Betty
B
Jones
Haydn T
HT
McConnell
Darryl B
DB
Mason
Andy M
AM
Nguyen
Van
V
Owens
Ian J
IJ
Parry
Nigel
N
Reece
Phillip A
PA
Shanahan
Stephen E
SE
Smith
Donna
D
Wu
Wen-Yang
WY
Tucker
Simon P
SP
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002850:Chromatography, Gel; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D006146:Guanidines; D007202:Indicators and Reagents; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011714:Pyrans; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects; D053243:Zanamivir
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D007202:Indicators and Reagents; D011714:Pyrans; D012794:Sialic Acids; D009439:Neuraminidase; D053243:Zanamivir