Hydrophobic benzoic acids as inhibitors of influenza neuraminidase.
Neuraminidase (NA) plays a critical role in the life cycle of influenza virus and is a target for new therapeutic agents. A new benzoic acid inhibitor (11) containing a lipophilic side chain at C-3 and a guanidine at C-5 was synthesized. The X-ray structure of 4-(N-acetylamino)-5-guanidino-3-(3-pentyloxy)benzoic acid in complex with NA revealed that the lipophilic side chain binds in a newly created hydrophobic pocket formed by the movement of Glu 278 to interact with Arg 226, whereas the guanidine of 11 interacts in a negatively charged pocket created by Asp 152, Glu 120 and Glu 229. Compound 11 was highly selective for type A (H2N2) influenza NA (IC50 1 microM) over type B (B/Lee/40) influenza NA (IC50 500 microM).
Atigadda
V R
VR
Department of Chemistry, University of Alabama at Birmingham, 35294, USA.
Brouillette
W J
WJ
Duarte
F
F
Babu
Y S
YS
Bantia
S
S
Chand
P
P
Chu
N
N
Montgomery
J A
JA
Walsh
D A
DA
Sudbeck
E
E
Finley
J
J
Air
G M
GM
Luo
M
M
Laver
G W
GW
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D011487:Protein Conformation
D000998:Antiviral Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D009439:Neuraminidase