Design, synthesis, and neuraminidase inhibitory activity of GS-4071 analogues that utilize a novel hydrophobic paradigm.
Structure-based design has led to the synthesis of a novel analogue of GS-4071, an influenza neuraminidase inhibitor, in which the basic amino group has been replaced by a hydrophobic vinyl group. An X-ray co-crystal structure of the new inhibitor (K(i)=45 nM) bound to the active site shows that the vinyl group occupies the same subsite as the amino group in GS-4071.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, QC, Canada. stephen.hanessian@umontreal.ca
Wang
Jianchio
J
Montgomery
Debra
D
Stoll
Vincent
V
Stewart
Kent D
KD
Kati
Warren
W
Maring
Clarence
C
Kempf
Dale
D
Hutchins
Charles
C
Laver
W Graeme
WG
D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology*; D000588:Amines / Q000737:chemistry; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000737:chemistry
D000081:Acetamides; D000588:Amines; D014753:Vinyl Compounds; D053139:Oseltamivir; D009439:Neuraminidase