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.

After attaching to the respiratory cell surface, the influenza virus, as already mentioned, can penetrate into the cell through more than one mechanism, and the final result is that the virions are internalized in an endosomal compartment [93] . According to the previous routes, virions can be packaged into CCPs and clathrin-coated vesicles (CCVs) or into caveosomes / macropinosomes. Subsequently, they are further processed into early endosomes (EEs) and into late endosomes (LEs) [94] . Endosomal trafficking usually follows influenza virus uptake. Virions are taken up into Rab-5/Vps4 and Rab-7/LAMP (lysosomal-associated membrane protein) positive endosomes. Rab-5/Vps4 and Rab-7 are Rab guanosine triphosphatases (GTPases) that are responsible for the processes of trafficking and fusion for EEs and LEs, respectively [95] [96] [97] . LAMPs are a series of proteins -3 isoforms are currently known, namely, LAMP1 (known also as CD107a), LAMP2, and LAMP3 (DC-LAMP, TSC403 or CD208) -that are involved in endosomal maturation [98] . Moreover, the expression of LAMP3 has been found to be predictive of the host's response to influenza [99] . Cullin-3 (Cul3) belongs to the Cullin-RING-ligase family (CRL). It functions as a scaffolding protein in the Bric-a-brac, Tramtrack, Broad-complex (BTB)-Cul3-Rbx1 ubiquitin E3 ligase complex and is involved in LE maturation and cargo trafficking [100, 101] . Endosomal trafficking is a complex multifaceted process that can be divided into three stages: stage I, which is actin-dependent, stage II, which is dynein-and microtubule-dependent, and stage III, which is microtubuledependent [102] .