7TIA

Crystal structure of SARS-CoV-2 3CL in complex with inhibitor NK01-14

7TIA の概要

• エントリーDOI: 10.2210/pdb7tia/pdb
• 分子名称: 3C-like proteinase nsp5, benzyl [(2S)-3-cyclopropyl-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-1-oxopropan-2-yl]carbamate, THIOCYANATE ION, ... (4 entities in total)
• 機能のキーワード: viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34287.10

構造登録者

Forouhar, F.,Liu, H.,Iketani, S.,Zack, A.,Khanizeman, N.,Bednarova, E.,Fowler, B.,Hong, S.J.,Mohri, H.,Nair, M.S.,Huang, Y.,Tay, N.E.S.,Lee, S.,Karan, C.,Resnick, S.J.,Quinn, C.,Li, W.,Shion, H.,Jurtschenko, C.,Lauber, M.A.,McDonald, T.,Stokes, M.E.,Hurst, B.,Rovis, T.,Chavez, A.,Ho, D.D.,Stockwell, B.R. (登録日: 2022-01-13, 公開日: 2022-05-04, 最終更新日: 2023-10-18)

主引用文献

Liu, H.,Iketani, S.,Zask, A.,Khanizeman, N.,Bednarova, E.,Forouhar, F.,Fowler, B.,Hong, S.J.,Mohri, H.,Nair, M.S.,Huang, Y.,Tay, N.E.S.,Lee, S.,Karan, C.,Resnick, S.J.,Quinn, C.,Li, W.,Shion, H.,Xia, X.,Daniels, J.D.,Bartolo-Cruz, M.,Farina, M.,Rajbhandari, P.,Jurtschenko, C.,Lauber, M.A.,McDonald, T.,Stokes, M.E.,Hurst, B.L.,Rovis, T.,Chavez, A.,Ho, D.D.,Stockwell, B.R.
Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.
Nat Commun, 13:1891-1891, 2022

PubMed Abstract: The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

PubMed: 35393402
DOI: 10.1038/s41467-022-29413-2

実験手法

X-RAY DIFFRACTION (1.64 Å)