9CED の概要
| エントリーDOI | 10.2210/pdb9ced/pdb |
| 分子名称 | 3C-like proteinase nsp5, N-[(2S)-1-{[(2S)-1-hydroxy-3-(2-oxo-1,2-dihydropyridin-3-yl)propan-2-yl]amino}-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide (3 entities in total) |
| 機能のキーワード | sars-cov-2, covalent inhibitor, protease, 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 | 34280.07 |
| 構造登録者 | |
| 主引用文献 | Kumar, V.,Zhu, J.,Chenna, B.C.,Hoffpauir, Z.A.,Rademacher, A.,Rogers, A.M.,Tseng, C.T.,Drelich, A.,Farzandh, S.,Lamb, A.L.,Meek, T.D. Dual Inhibitors of SARS-CoV-2 3CL Protease and Human Cathepsin L Containing Glutamine Isosteres Are Anti-CoV-2 Agents. J.Am.Chem.Soc., 147:1631-1648, 2025 Cited by PubMed Abstract: SARS-CoV-2 3CL protease (Main protease) and human cathepsin L are proteases that play unique roles in the infection of human cells by SARS-CoV-2, the causative agent of COVID-19. Both proteases recognize leucine and other hydrophobic amino acids at the P position of a peptidomimetic inhibitor. At the P position, cathepsin L accepts many amino acid side chains, with a partial preference for phenylalanine, while 3CL-PR protease has a stringent specificity for glutamine or glutamine analogues. We have designed, synthesized, and evaluated peptidomimetic aldehyde dual-target (dual-acting) inhibitors using two peptide scaffolds based on those of two Pfizer 3CL-PR inhibitors, , and . Our inhibitors contain glutamine isosteres at the P position, including 2-pyridon-3-yl-alanine, 3-pyridinyl-alanine, and 1,3-oxazo-4-yl-alanine groups. Inhibition constants for these new inhibitors ranged from = 0.6-18 nM (cathepsin L) and = 2.6-124 nM (3CL-PR), for which inhibitors with the 2-pyridon-3-yl-alanal substituent were the most potent for 3CL-PR. The anti-CoV-2 activity of these inhibitors ranged from EC = 0.47-15 μM. X-ray structures of the peptidomimetic aldehyde inhibitors of 3CL-PR with similar scaffolds all demonstrated the formation of thiohemiacetals with Cys, and hydrogen-bonding interactions with the heteroatoms of the pyridon-3-yl-alanyl group, as well as the nitrogen of the N-terminal indole and its appended carbonyl group at the P position. The absence of these hydrogen bonds for the inhibitors containing the 3-pyridinyl-alanyl and 1,3-oxazo-4-yl-alanyl groups was reflected in the less potent inhibition of the inhibitors with 3CL-PR. In summary, our studies demonstrate the value of a second generation of cysteine protease inhibitors that comprise a single agent that acts on both human cathepsin L and SARS-CoV-2 3CL protease. Such dual-target inhibitors will provide anti-COVID-19 drugs that remain active despite the development of resistance due to mutation of the viral protease. Such dual-target inhibitors are more likely to remain useful therapeutics despite the emergence of inactivating mutations in the viral protease because the human cathepsin L will not develop resistance. This particular dual-target approach is innovative since one of the targets is viral (3CL-PR) required for viral protein maturation and the other is human (hCatL) which enables viral infection. PubMed: 39746101DOI: 10.1021/jacs.4c11620 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.82 Å) |
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