Carbocycles related to oseltamivir as influenza virus group-1-specific neuraminidase inhibitors. Binding to N1 enzymes in the context of virus-like particles.
We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (N1) activity indicate that several candidates are inhibitors, with K(i) values in the 10(-5)-10(-8) M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with K(i) values of 1.5 × 10(-9) and 4.6 × 10(-10) M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (K(i) = 2.6 μM vs 0.07 μM) of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.
Mohan
Sankar
S
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
McAtamney
Sarah
S
Haselhorst
Thomas
T
von Itzstein
Mark
M
Pinto
Brian Mario
BM
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D020134:Catalytic Domain; D009980:Influenza A virus / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053139:Oseltamivir / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry; D014771:Virion / Q000187:drug effects* / Q000201:enzymology
D000998:Antiviral Agents; D014230:Triazoles; D053139:Oseltamivir; D009439:Neuraminidase