Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses.
Unlike the group-2 neuraminidase, the group-1 neuraminidase of influenza virus possesses a flexible loop (the 150-loop) and a cavity (the 150-cavity) adjacent to the active site, and renders a conformational change from the 'open' form to the 'closed' form on binding with substrate (sialo-glycoprotein) or inhibitor (e.g., zanamivir). Zanamivir derivative 8a having an extended (piperazinocarbonyl)propyl substituent at the internal N-position of the guanidino group is designed as a possible inhibitor on the basis of computer docking to the open form of N1 subtype neuraminidase. Indeed, compound 8a exhibits strong neuraminidase inhibition and good anti-influenza activity against H1N1 virus with IC(50)=2.15microM and EC(50)=0.77microM, respectively. This study may provide a clue to future design of better group-1 neuraminidase inhibitors.
Wen
Wen-Hsien
WH
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
Wang
Shi-Yun
SY
Tsai
Keng-Chang
KC
Cheng
Yih-Shyun E
YS
Yang
An-Suei
AS
Fang
Jim-Min
JM
Wong
Chi-Huey
CH
D000998:Antiviral Agents / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry; D053118:Influenza A Virus, H1N1 Subtype; D020128:Inhibitory Concentration 50; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000201:enzymology*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase; D053243:Zanamivir