Recent progress in structure-based anti-influenza drug design

Abstract

Seasonal and pandemic influenza have caused high morbidity and mortality worldwide. Recent emergence of influenza A H5N1 and H1N1 strains has heightened concern, especially as a result of their drug resistance. The life cycle of influenza viruses has been well studied and nearly all the viral proteins are becoming potential therapeutic targets. In this review, we present an overview of recent progress in structure-based anti-influenza drug design, paying close attention to the increasing role of computation and strategies for overcoming drug resistance.

Figure 1

(a) Hemagglutinin (HA) trimer, bound to a sialic acid, N-acetylneuraminic acid (Neu5Ac); tert-butylhydroquinone (TBHQ); or a designed protein, HB36 (PDB entries 3M5I, 3EYK and 3R2X, respectively). Two of the HA monomers are represented as magenta and yellow surfaces, and the third as a cartoon, with HA1 and HA2 in light and dark blue, respectively. (b) Small molecules that either target the sialic acid binding site (Neu5Ac and compounds 1 and 2) or inhibit membrane fusion (TBHQ and compound 3). {8. AU: I am unable to edit Fig 1. Please follow DDT house style and use sentence case throughout: i.e. Sialic acid}

Figure 2

(a) Neuraminidase inhibitors. (b) The active site of N1 (light blue) and N9 (yellow) neuraminidases (PDB entries 2HU0 and 2C4A, respectively). The N1 structure has the 150-loop in the open conformation, even with oseltamivir (shown with carbons in green) bound. The 150-loop and 430-loop of N1 and N9 are shown in dark blue and in orange, respectively. N1 sidechains interacting with oseltamivir are also shown. {9. AU: I am unable to edit Fig 2. Please follow DDT house style and close up in-house nomenclature for compounds: i.e. A315675. Because this is DDT house style please note that I have made this change in your manuscript}

Figure 3

(a) The M2 conductance domain, comprising the transmembrane and amphipathic helices (PDB entry 2L0J). The bound amantadine (shown with carbons in magenta) is from PDB entry 2KQT. Sidechains prone to drug-resistant mutations or functionally important are shown. Yellow shade represents the viral membrane. (b) M2 channel blockers. {10. AU: I am unable to edit Fig 3. Please follow DDT house style and close up in-house compound nomenclature: i.e. BL1743, please also use the correct symbol for the minus sign on Cl^–}

Figure 4

M1 and nuclear export protein (NEP) as adaptor proteins between a ribonucleoprotein particle and Crm1.

Figure 5

(a) Small molecules that induce nucleoprotein (NP) aggregation (nucleozin) and target the tail-loop binding pocket (compound 6) or the RNA binding groove (compound 7). (b) Structure of an NP monomer, with the tail loop (in magenta) of an adjacent NP molecule buried (PDB entry 2IQH). A salt bridge important for tail-loop binding is highlighted in the inset. Arginine sidechains defining the RNA binding groove are also shown. {11. AU: I am unable to edit Fig 5. Please follow DDT house style and use sentence case throughout: i.e. Tail-loop binding pocket}

Figure 6

(a) Domain organizations of PA, PB1, PB2, M1, NEP and NS1. (b) Left: endonuclease domain of PA (PDB entry 3HW5). The Mg²⁺ ion and the surrounding residues defining the active site are shown. Right: C-terminal domain of PA bound with the N-terminal region of PB1 (PDB entry 3CM8). (c) The N-terminal (light blue) and middle (cyan) domains of M1 (PDB entry 1EA3). Cationic residues, including those in the nuclear localization signal motif ¹⁰¹RKLKR¹⁰⁵ are displayed. These residues are involved in NEP binding. (d) The C-terminal domain of NEP (PDB entry 1PD3). W78 and surrounding anionic residues involved in M1 binding are shown. (e) Left: N-terminal domain of NS1 bound to double-stranded RNA (PDB entry 2ZKO). Two cationic residues in the binding interface are displayed. Right: effector domain of NS1 bound to two copies of the second and third zinc fingers of CPSF30 (PDB entry 2RHK). The zinc fingers are in yellow and green.

Figure 6

(a) Domain organizations of PA, PB1, PB2, M1, NEP and NS1. (b) Left: endonuclease domain of PA (PDB entry 3HW5). The Mg²⁺ ion and the surrounding residues defining the active site are shown. Right: C-terminal domain of PA bound with the N-terminal region of PB1 (PDB entry 3CM8). (c) The N-terminal (light blue) and middle (cyan) domains of M1 (PDB entry 1EA3). Cationic residues, including those in the nuclear localization signal motif ¹⁰¹RKLKR¹⁰⁵ are displayed. These residues are involved in NEP binding. (d) The C-terminal domain of NEP (PDB entry 1PD3). W78 and surrounding anionic residues involved in M1 binding are shown. (e) Left: N-terminal domain of NS1 bound to double-stranded RNA (PDB entry 2ZKO). Two cationic residues in the binding interface are displayed. Right: effector domain of NS1 bound to two copies of the second and third zinc fingers of CPSF30 (PDB entry 2RHK). The zinc fingers are in yellow and green.