Taking aim at a moving target - inhibitors of influenza virus Part 1: virus adsorption, entry and uncoating Nicholas A. Meanwell and Mark Krystal Annual epidemics of influenza virus infection are respon- sible for considerable morbidity and mortality, and pan- demics are much more devastating. Considerable knowledge of viral infectivity and replication has been acquired, but many details have yet to be elucidated and the virus remains a particularly challenging target for drug design and development. In this two part review, the current status of influenza research is summarized in the context of inhibitor design and discovery, and recent advances in the search for clinically effective drug therapy are detailed. The first part addresses virus adsorption, entry and uncoating; the second part, to be published in the September issue of Drug Discovery Today, discusses aspects of virus replication, packaging and release. A nnual epidemic outbreaks of influenza virus infec- tion continue to be an important cause of mor- bidity and mortality, with the young and elderly populations being particularly vulnerablerJ. Because the options for the therapeutic treatment of influenza infections are currently limited, a prophylactic strategy has been adopted that relies on the annual implementation of a vaccination program. However, vaccination has provided only limited control over influenza infectivity due to incomplete immunization coverage of individuals considered to be at risk and the propensity for the virus to escape the immune system. The latter is a property inherent to the structural composition and mode of replication of influenza viruses, which are mem- bers of the Orthomyxoviradae family of enveloped viruses. The viral envelope contains two major surface antigenic proteins, hemagglutinin (HA) and neuraminidase (NA): along with a minor component, the M2 protein, which is a small hydrophobic protein found in type A influenza virus strains and which functions as an ion channel (Figure 1). Type B influenza strains contain an analogous protein, designated NB, which is encoded by a second reading frame on the NA gene. Under the electron microscopes, the HA and NA pro- teins appear as spikes on the virion surface, and recurrent influenza epidemics are associated with antigenic changes in these molecules. Layered immediately beneath the lipid en- velope of the virus particle is the matrix (M) protein, which surrounds the core of ribonucleoprotein (RNP). The RNP con- sists of a genome of eight different RNA segments of negative polarity which are coated with nucleoprotein (NP), forming helical structures that contain, as minor components, the three viral polymerase proteins PB2, PBl and PA (Ref. 4). The virus genome also encodes two proteins, NSl and NS2, which are not found in mature virions (Figure 1). Nicholas A. Meanwell* and Matk +I, Departments of Chemistry and Virology, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.*tel: +I 203264 6679, fax: +I 2032647702; e-mail: Nicholas A. MeanwellQccmail.bms.com 316 CopyrIght Elsevler Science Ltd All rights reserved. 1359.6446/96/$15 00. PII: S1359-6446(96110029-5 DDT Vol. 1, NO. 8 August 1996