Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: influenza life-cycle and currently available drugs

Influenza is a contagious respiratory acute viral disease charac- terized by a short incubation period, high fever and respiratory and systemic symptoms. The burden of influenza is very heavy. Indeed, the World Health Organization (WHO) estimates that annual epidemics affect 5-15% of the world?s population, causing up to 4-5 million severe cases and from 250,000 to 500,000 deaths. In order to design anti-influenza molecules and compounds, it is important to understand the complex replication cycle of the influenza virus. Replication is achieved through various stages. First, the virus must engage the sialic acid receptors present on the free surface of the cells of the respiratory tract. The virus can then enter the cells by different routes (clathrin-mediated endocytosis or CME, caveolae-dependent endocytosis or CDE, clathrin-caveolae-independent endocytosis, or macropinocyto- sis). CME is the most usual pathway; the virus is internalized into an endosomal compartment, from which it must emerge in order to release its nucleic acid into the cytosol. The ribonucleo- protein must then reach the nucleus in order to begin the pro- cess of translation of its genes and to transcribe and replicate its nucleic acid. Subsequently, the RNA segments, surrounded by the nucleoproteins, must migrate to the cell membrane in order to enable viral assembly. Finally, the virus must be freed to invade other cells of the respiratory tract. All this is achieved through a synchronized action of molecules that perform multi- ple enzymatic and catalytic reactions, currently known only in part, and for which many inhibitory or competitive molecules have been studied. Some of these studies have led to the devel- opment of drugs that have been approved, such as Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Laninamivir, Ribavirin and Arbidol. This review focuses on the influenza life- cycle and on the currently available drugs, while potential anti- viral compounds for the prevention and treatment of influenza are considered in the subsequent review