Development of neuraminidase inhibitors as anti-influenza virus drugs

Structure-based design and synthesis of potent influenza virus neuraminidas e inhibitors are now being evaluated in human trials as anti-influenza viru s drugs. The first drug of this class, Relenza(TM) (Zanamivir/GG167), is no w awaiting pharmaceutical evaluation and registration in Australia, Europe, and North America for both treatment and prophylaxis of influenza. The tar get for the drug is the active site of neuraminidase, which is a pocket tha t has been totally conserved in both Type A and B influenza in all known su btypes of influenza (animal and human). Mutations in residues that surround this conserved pocket allow the virus to escape binding to circulating ant ibodies that recognise the molecular surface around the active site of the wild-type virus. High-affinity neuraminidase inhibitors have been designed that interact only with the conserved active site residues. The design of t hese sialic acid analogues was based on the crystal structure of influenza virus neuraminidase and its complex with N-acetyl neuraminic acid (sialic a cid) and 2-deoxy-2,3-dehydro-N-acetyl neuraminic acid. These novel inhibito rs are highly specific for influenza neuraminidase, and have been shown to inhibit influenza virus replication in both cell culture and animal models. The development of drugs against a rapidly mutating organism like influenz a has to address to the possibility of emerging drug resistance. This is ex amined in the light of drug resistant mutants selected after in vitro passa ging of virus in the presence of neuraminidase inhibitors. Drug Dev. Res. 4 6:176-196, 1999. (C) 1999 Wiley-Liss, Inc.