Showing papers by "Peter M. Colman published in 1999"

A novel approach to antiviral therapy for influenza

Abstract: The influenza glycoprotein, neuraminidase, destroys sialic acid-containing receptors on the surface of infected cells and on progeny virions. This activity facilitates the elution of newly budded virus from the infected cell surface and thus contributes to the viral burden in the host. On the basis of the three-dimensional structure of neuraminidase and the structure of the enzyme-product complex, novel analogues of the product (sialic acid, Neu5Ac) were designed and were shown to be potent inhibitors of neuraminidase in vitro and in vivo. Zanamivir (4-guanidino-Neu5Ac2en) is one of the most potent of the sialic acid analogues described to date. It is broadly inhibitory of all type A and B neuraminidases, probably because one of its design features was the requirement that it should interact only with strain-invariant amino acids inside the active site of the enzyme. Inhibition of neuraminidase translates into antiviral activity in tissue culture, in animal models of influenza and in both experimental and naturally acquired influenza in humans. Zanamivir is a minimal modification of the natural ligand (Neu5Ac) of the enzyme. This feature is expected to minimize the viability of drug-resistant virus that might arise through mutations in the enzyme active site. Studies to date of drug-resistant variants selected in tissue culture confirm this expectation. To deliver zanamivir directly to the lungs of patients the agent has been formulated for inhalation using a modified Diskhaler, which ensures high local concentrations and maximizes inhibition of viral neuraminidase.