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.

RIG-I (Retinoic acid-Inducible Gene I). Therefore, it blocks PACT/RIG-Imediated activation of IFN-I [116, 117] . Moreover, it binds latent protein kinase PKR (Protein Kinase R, also known as Protein kinase RNA-activated or interferoninduced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 -EIF2AK2), whose activation would inhibit viral protein translation and synthesis [118] , and also TRIM25 (tripartite motif-containing protein 2) [119, 120] . Recently, it has been shown to interact with an array of host proteins, such as interleukin-6 receptor (IL-6R), MHC class I HLA-B, cathepsin B, ubiquitin, and adenosine deaminase acting on RNA (ADAR1) [121] . With regard to M2 ion channel activity, the heart of this mechanism is the HxxxW motif of the inner transmembrane (TM) residues [122] [123] [124] [125] . In this HxxxW motif, Histidine 37 putatively acts as the pH sensor and, when the pH is low, the protonation of the imidazolic ring destabilizes TM packing because of electrostatic repulsion. Tryptophan 41, which acts as a primary gate, rotates, becomes unlocked from Aspartic acid 44 ("the channel lock") and, being now parallel to the axis of the pore, makes the protons flow. By contrast, Valine 27 acts as a secondary gate (the so-called "Valine 27 valve"); its importance has been confirmed only recently by the multi-scale simulation carried out by Liang and coll. [126] . On the basis of the exact role of the Histidine 37 tetrad, two models have been proposed: the shutter model, in which the biprotonated charge of Histidine 37 does not change during the proton flux (proton diffusion is coupled with water wire via the Grotthuss mechanism), and the shuttle model, in which the protonation status of Histidine 37 is subject to changes during excess proton transfer [127] . However, the exact mechanism of highly selective transport of protons is not known. Acidification is enhanced by the viral activation of the PI3K cascade [76] .