29DA
Crystal structure of enterovirus D68-3Cpro in complex with RK-496
This is a non-PDB format compatible entry.
Summary for 29DA
| Entry DOI | 10.2210/pdb29da/pdb |
| Descriptor | Genome polyprotein, 1-[(3~{S},6~{S},7~{R})-7-oxidanyl-4,8-bis(oxidanylidene)-6-[[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]methyl]-5,9-diazabicyclo[14.3.1]icosa-1(19),16(20),17-trien-3-yl]-3-[2,2,2-tris(fluoranyl)ethyl]urea (3 entities in total) |
| Functional Keywords | 3cpro, enterovirus, inhibitor, viral protein |
| Biological source | Enterovirus |
| Total number of polymer chains | 1 |
| Total formula weight | 21580.46 |
| Authors | |
| Primary citation | Akula, R.K.,El Kilani, H.,Metzen, A.,Joshi, S.,Durmaz, H.,Veenstra, R.,Roske, J.,Hurdiss, D.L.,Van Kuppeveld, F.J.M.,Rox, K.,Hilgenfeld, R.,Bronstrup, M. Structure-based macrocyclization of alpha-ketoamides leads to potent inhibitors of coronaviral and enteroviral proteases. Commun Chem, 9:-, 2026 Cited by PubMed Abstract: Viral proteases represent validated targets for direct-acting antivirals and the treatment of associated infections. In co-crystal structures of M of SARS-CoV-2 with peptidomimetic inhibitors, we noticed a spatial proximity of sidechains filling the S1' and S2 pockets, as well as those filling S3 and S1 pockets. To enhance molecular rigidity, the proximal residues were conformationally fixed by macrocyclization. We report the synthesis of two macrocyclic series, i.e. exocyclic nitriles with linked P3 and P1 residues and endocyclic α-ketoamides with linked P1' and P2 residues, and characterize their binding modes and bioactivities. The 17-membered macrocyclic α-ketoamide 20 f inhibited M (IC₅₀ = 370 nM) and exerted anti-SARS-CoV-2 effects (EC₅₀ = 1.9 μM). Leveraging structural similarities between M and the 3C of enterovirus D68, we describe with two co-crystal structures how α-ketoamide macrocycles bound to and inhibited the enteroviral protease. Notably, 20 f exhibited very potent antiviral activities with EC₅₀'s of 33, 133, and 146 nM against EV-D68, EV-A71, and CVB3, respectively. The study demonstrates how broad-spectrum activity can be achieved with direct-acting antivirals. PubMed: 42562838DOI: 10.1038/s42004-026-02151-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.08 Å) |
Structure validation
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