9T55

Crystal structure of SARS-CoV-2 Mpro in complex with RK-384

これはPDB形式変換不可エントリーです。

9T55 の概要

• エントリーDOI: 10.2210/pdb9t55/pdb
• 分子名称: 3C-like proteinase nsp5, ~{N}-[(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-phenyl-propanamide (3 entities in total)
• 機能のキーワード: sars-cov-2, mpro, inhibitor, complex, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34260.12

構造登録者

El Kilani, H.,Hilgenfeld, R. (登録日: 2025-11-04, 公開日: 2026-08-19)

主引用文献

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

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: 42562838
DOI: 10.1038/s42004-026-02151-y

実験手法

X-RAY DIFFRACTION (1.75 Å)