Anti-influenza drugs targeting trimeric RNA polymerase complex: From development to clinics

Figure 1. Structure and timeline of approved anti-influenza drugs targeting the polymerase complex.

Figure 2. Schematic representation of influenza virus particle (A) and viral ribonucleoprotein complex (B). (C) The structure of trimeric influenza RNA polymerase and the inhibitor binding sites on PA, PB1, or PB2. The complete heterotrimeric RNA polymerase X-ray structure (PDB code 6QNW) is shown: PA in pale green, PB1 in bright orange, PB2 in aquamrine. PA endonuclease binds with BXA. (PDB code 6FS6). PB1 with vRNA (the two Mg2+ at RNA polymerase catalytic site were shown in green balls, and RNA around the catalytic site was highlighted in purple, PDB code 6SZV). PB2 cap binds to VX787 (PDB code 6EUV).

Figure 3. Schematics and structure of the PA subunit (PDB code 6QNW).

Figure 4. (A) Conversion of prodrug BXM and its active metabolite BXA, which is hydrolyzed by arylacetamide deacetylase. (B) Resistance mutation sites of BXA were highlight in red and black dot (PDB: 6FS6). (C, D) The binding mode of BXA to PA (H3N2) subunit. Yellow sticks represent BXA, gray sticks represent amino acid residues, black dashed lines indicate coordination bonds formed between Mn2+ and BXA as well as the amino acid residues, yellow dashed lines represent hydrogen bonds, and blue dashed lines indicate π–π interactions. (E) The superimposed structure of the BXA binding site in wt I38 PA and T38 PA (PA I38T (PDB: 6FS7) is shown (structures are depicted in green for I38 PA bound to BXA and in white for T38 PA bound to BXA).

Figure 5. Schematics and structure of PB1 subunit (PDB code 6QNW).

Scheme 1. The activation of favipiravir: Favipiravir initial conversion to the ribosyl-5′-monophosphate form (T-705 RMP) catalyzed by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Further phosphorylations produce the active favipiravir-RTP (T-705 RTP).

Figure 6. Schematics and structure of PB2 subunit (PDB code 6QNW).

Figure 7. The binding mode of pimodivir to PB2 of IAV (PDB: 6EUV) and PB2 of IBV (PDB: 6EUX) is shown in Cartoons (A) and binding sites (B). (C) Residues liable to potential substitutions associated with resistance to pimodivir are displayed as green sticks: F404 (to Y), S324 (to I/N/R), Q306 (to H), N510 (to T). (D) The alignment and difference of pimodivir binding site of IAV PB2 (residues are depicted in gold and pimodivir in magenta) and IBV PB2 with VX-787N (depicted in white).

Figure 8. Structure of pimodivir and onradivir (A) and the predicted binding mode of onradivir to the cap binding domain of IAV PB2 (B). Representative structures illustrating key interactions between the onradivir with PB2 (C). Onradivir was docked into PB2 (PDB: 6EUV) and visualized using PyMOL 2.0 software.