Serendipitous discovery of a potent influenza virus a neuraminidase inhibitor.

We have previously reported a potent neuraminidase inhibitor that comprises a carbocyclic analogue of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3-pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay (Ki =0.46 nM; Ki (zanamivir) =0.

Structural basis for a class of nanomolar influenza A neuraminidase inhibitors.

The influenza virus neuraminidase (NA) is essential for the virus life cycle. The rise of resistance mutations against current antiviral therapies has increased the need for the development of novel inhibitors. Recent efforts have targeted a cavity adjacent to the catalytic site (the 150-cavity) in addition to the primary catalytic subsite in order to increase specificity and reduce the likelihood of resistance.

Exploitation of the catalytic site and 150 cavity for design of influenza A neuraminidase inhibitors.

We report here the exploitation of the 150 cavity in the active site of influenza A viral neuraminidases for the design of novel C-6 triazole-containing Tamiflu derivatives. A general and convenient synthetic route was developed by utilizing a highly substituted cyclic Baylis-Hillman acetate as an active precursor for azide substitution via suprafacial allylic azide [3,3]-sigmatropic rearrangement. Virus replication inhibitory assays in vitro of these triazole derivatives containing either an amino or guanidino function indicated that the guanidinium compound showed the higher efficacy against a strain with N2 subtype at a concentration of 2 × 10(-5) M but did not inhibit replication of a strain with N1 subtype even at a concentration of 10(-4) M.

Mechanism-based covalent neuraminidase inhibitors with broad-spectrum influenza antiviral activity.

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro.

Replication inhibition activity of carbocycles related to oseltamivir on influenza A virus in vitro.

We have recently demonstrated that newly synthesized oseltamivir derivatives that contain a substituted triazole ring at the C-5 amino group interact with the 150 cavity found specifically in the group-1 neuraminidase (NA) subtypes of influenza A virus. These compounds exhibited in vitro inhibition activity of a group-1 NA enzyme incorporated in virus-like particles (VLPs). In the current study, we tested these nine triazole-containing carbocycles as well as an amino- and a guanidino-substituted derivative in virus replication inhibitory assays in vitro.