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

GASPARINI, R.; AMICIZIA, D.; LAI, PL.; BRAGAZZI, NL.; PANATTO, D.

The replication cycle of the virus (Fig. 1 ) is a complex, highly dynamic, biological process which consists of the following steps: 1) attachment of the virion to target cells and receptor binding (virus adsorption); 2) internalization into cellular regions by means of clathrin-mediated endocytosis (CME), caveolae-dependent endocytosis (CDE), clathrin-caveolae-independent endocytosis, and macropinocytosis; 3) endosomal trafficking via endosomes / caveosome / macropinosome / lysosomes to the perinuclear compartment; 4) pH-dependent fusion of viral and endosomal / organellar membranes; 5) uncoating; 6) nuclear importation; 7) transcription and replication; 8) nuclear exportation; 9) protein synthesis; 10) post-translational processing and trafficking; 11) viral progeny assembly and packaging; 12) budding; and 13) release (modified from [48] ). The cells infected by the influenza virus are: alveolar and bronchial epithelial tissue (BET) cells, alveolar macrophages (AM), lung epithelial tissue (LET) cells and, in particular, type II pneumocytes, plasmacytoid dendritic cells (pDCs) and natural killer cells (NKs) [49, 50] . Influenza virus is able to activate Endoplasmic Reticulum (ER) stress, caspase pathway [51] or to finely tune host secreted molecules, such as lung mucins [52] , in order to avoid being trapped and subsequently eliminated. Moreover, it recruits host factors and misuses them [53] . Although the mechanisms of influenza virus replication are not fully understood, scientific projects for new drugs against influenza cannot ignore the biological cycle of this virus.