Advances in Antiviral Drug Development Targeting Enteroviruses: From Viral Proteins to Host Factors

Figures

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  Figure 1. Life cycle of enteroviruses.

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  Figure 2. In panels (A–C), nitrogen and oxygen atoms are shown in blue and red, respectively, and the inhibitor carbon atoms are shown in green. (A) Crystal structure of HRV2 VP1 complexed with compound BTA798 (6) (PDB:3VDD) and the chemical structure of BTA798. (B) Crystal structure of EV-A71 VP1 complexed with inhibitor NLD (9) (PDB:4CEY) and the chemical structure of NLD. (C) Crystal structure of EV-A71 VP1 complexed with inhibitor ALD (10) (PDB:4CEW) and the chemical structure of ALD. (D) Protein structure of PF4-C15 (PDB:1WAB). (E) Chemical structural formula of the EVs capsid protein inhibitor.

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  Figure 3. (A) Chemical structure of inhibitors targeting 2A protein in EVs. (B) Docking model of telaprevir/Jun11762 with EV-D68 2A protease and the chemical structure of telaprevir/Jun11762. (Adapted with permission from ref [56]. Copyright © 2023 American Chemical Society.) In panel (B), the ligand is shown in green, with nitrogen and oxygen atoms shown in blue and red, respectively.

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  Figure 4. Chemical structure of inhibitors targeting 2B protein in EVs.

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  Figure 5. (A) Crystal structure of CV-B3 with fluoxetine (PDB:6S3A) and the chemical structure of fluoxetine. (B) The chemical structure formula of the inhibitor targeting the 2C protein in EVs. In panel (B), the ligand is shown in green, with nitrogen and oxygen atoms shown in blue and red, respectively. (C) Structural interactions between EV-D68 2C protein and Jun571/Jun6504, along with chemical structural formulas of compounds. ([75], licensed under CC BY 4.0.).

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  Figure 6. (A) X-ray crystal structure of the C-terminal Golgi-dynamics domain (GOLD) of ACBD3 in complex with the cytoplasmic domain of the EV-A71 3A protein (PDB:6HLW). ACBD3 is shown in gray, and the EV-A71 3A protein is shown in a blue-to-purple color scheme. (B) Chemical structure of the inhibitor targeting the 3A protein in EVs.

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  Figure 7. In panels (A–F), nitrogen and oxygen atoms are shown in blue and red, respectively, and the inhibitor carbon atoms are shown in green. (A) Crystal structure of the EV-A71 3C protease–rupintrivir complex (PDB:5HXF) and chemical structure of rupintrivir. (B) Crystal structures of EV-D68 3C protease in complex with AG7404 (PDB:8W3M) and chemical structure of AG7404. (C) Crystal structures of EV-A71 3C protease in complex with NK-1.8k (PDB:5GSO) and chemical structure of NK-1.8k. (D) Crystal structure of EV-A71-3C protease with a novel macrocyclic compound (PDB:6LKA) and the chemical structure of compound 4. (E) Crystal structures of EV-D68 3C protease in complex with GC376 (PDB:8W3T) and chemical structure of GC376. (F) Crystal structures of EV-D68 3C protease in complex with quercetin (PDB:8GQT) and chemical structure of quercetin. (G) Chemical structure of the 3C protein inhibitor for EVs.

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  Figure 8. In panel (B), nitrogen and oxygen atoms are shown in blue and red, respectively, and the inhibitor carbon atoms are shown in green. (A) Chemical structure of inhibitors targeting 3D proteins in EVs. (B) Crystal structure of CV-B3-3D polymerase in complex with GPC-N114 inhibitor (PDB:4Y2A) and the chemical structure of GPC-N114.

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  Figure 9. Viral release inhibitors: Chemical structure of Retro-2cycl and Retro-2.1.

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  Figure 10. (A) The chemical structure of IRES inhibitors. (B) Solution NMR structure of EV-A71 IRES in complex with DMA-135 (PDB:6XB7). DMA-135 is shown in green, the EV-A71 IRES RNA backbone is shown in orange, and the local RNA nucleotides around the binding site are shown in blue/gray.

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  Figure 11. In panels (A–F), the ligand is shown in green, with nitrogen and oxygen atoms shown in blue and red, respectively. (A) Crystal structure of the human eIF4A-1 in complex with silvestrol (PDB:9AVR) and chemical structure of silvestrol. (B) Crystal structures of the human eIF4A-1 in complex with rocaglamide A (PDB:5ZC9) and chemical structure of rocaglamide A. (C) Crystal structures of the HSP90 in complex with geldanamycin (PDB:1YET) and chemical structure of geldanamycin. (D) Crystal structures of the DHODH in complex with ML390 (PDB:5K9C) and chemical structure of ML390. (E) Crystal structures of the DHODH in complex with brequinar (PDB:1D3G) and chemical structure of brequinar. (F) Crystal structures of MEK1 in complex with U0126 (PDB:3EQH) and chemical structure of U0126. (G) Chemical structure of the host-targeting antivirals inhibitor for EVs. (H) Chemical structure of the endolysosomal pathway antivirals inhibitor for EVs.