Influenza Viruses: Harnessing the Crucial Role of the M2 Ion-Channel and Neuraminidase toward Inhibitor Design

Figure 1. Structure of influenza A virus showing the two major surface glycoproteins (hemagglutinin (HA) and neuraminidase (NA)), the nucleocapsid and polymerase proteins (NP, PB1, PB2, and PA), the matrix proteins (M1 and M2), the non-structural proteins (nuclear export protein (NEP)), lipid bilayer and segmented negative-strand RNA genes [48].

Figure 2. The replication cycle of influenza virus, illustrating seven discernible phases: (1) attachment; (2) endocytosis; (3) uncoating and membrane fusion; (4) transcription of the viral RNA; (5) translation of viral proteins; (6) replication of the viral RNA; and (7) virion budding and release [60].

Figure 3. Three-dimensional structure of the influenza A M2 (AM2) ion channel. (A) A monomer of the AM2 protein transmembrane domain (TMD) displaying channel facing amino acid residues; (B) Organization of four TMDs, and the alignment of pore-lining residues. For clarity, three AM2 monomers are shown to expose the sidechains of the pore-lining residues. The NMR structure with PDB ID 2RLF was used (prepared by authors).

Figure 4. Model for AM2 channel acid activation and proton conductance displaying conformation change from closed to open conformers [148]. For clarity, only two helices and one protonation state are shown.

Figure 5. Adamantane and its amine analogues: amantadine (1), rimantadine (2), R-rimantadine (2-R) and S-rimantadine (2-S) (prepared by authors).

Figure 6. (A) The structure of NA as a tetramer of 4 identical monomers. Each monomer consists of 4 different structural domains called catalytic head, stalk, transmembrane and the cytoplasmic tail. The head domain structure was generated in Pymol using structural information from protein data bank code 4GZX [182]. (B) Top-down view of the NA tetramer. (C) The active site of NA in complex with Zanamivir is represented. Residues involved in catalysis are shown as green sticks (adapted with permission from ref. [183]). (D) Tree of known influenza virus NAs and NA-like proteins (N10 and N11). Influenza NAs cluster into group 1 (N1, N4, N5, N8) and group 2 NAs (N2, N3, N6, N7, N9). Influenza B NAs as well as the NA-like proteins (from sequences found in bats) form their own clusters (adapted with permission from ref. [184]).

Figure 7. Diagram of NA active site with dehydrodeoxy-N-acetylneuraminic acid (DANA) inhibitor showing the five inhibitor binding sub-sites and nearby critical residues [188].

Figure 8. Catalytic Mechanism of NA showing four major steps of NA Inhibitors [190].

Figure 9. Chemical structure of sialic acid for treatment and prophylaxis of influenza infection (a), DANA (b), zanamivir (c), oseltamivir (d), peramivir (e), and laninamivir (f) (prepared by authors).