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.

otein Kinase C), PTEN (Phosphatase and tensin homolog) pathways [76] . Macropinocytosis can be activated by cell growth factors such as the Epidermal Growth Factor (EGF) or Nerve Growth Factor (NGF) or can be induced by phorbol esters. Macropinocytosis is Rac1-, PAK1-(p21-activated kinase type 1), cholesterol-and actin-dependent, since it extensively reorganizes the plasma membrane and implies energy mechanisms, such as Na + /H + exchanger (NHE) activity [77, 78] . Also other pathogens such as Ebolavirus [79, 80] , arenavirus [81] , adenovirus [82, 83] , HPV (Human Papillomavirus) [84] , HIV (Human Immunodeficiency Virus) [85] , Escherichia coli [86] , Trypanosoma cruzi [87] , vaccinia virus [88] , African Swine Fever virus [89] , RSV (Respiratory Syncytial Virus) [90] and HCV (Hepatitis C Virus) [91] , among the others, use macropinocytosis as additional entry pathways. These different routes (CME, CDE, non-clathrin noncaveolae endocytosis and macropinocytosis) result in different internalization yields and may be related to the different degrees of virulence and pathogenicity of influenza strains [92] .