4OW0

X-Ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-Like Proteases

4OW0 の概要

• エントリーDOI: 10.2210/pdb4ow0/pdb
• 関連するPDBエントリー: 4OVZ
• 分子名称: papain-like protease, ZINC ION, N-[(3-fluorophenyl)methyl]-1-[(1R)-1-naphthalen-1-ylethyl]piperidine-4-carboxamide, ... (6 entities in total)
• 機能のキーワード: cov, coronavirus, hcov, human coronavirus, sars, severe acute respiratory syndrome, mers, middle east respiratory syndrome, plpro, papain-like protease; inhibitor, complex, dub, deubiquitinating enzyme, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: SARS coronavirus
• 細胞内の位置: Non-structural protein 3: Host membrane ; Multi-pass membrane protein . Non-structural protein 4: Host membrane ; Multi-pass membrane protein . Non-structural protein 6: Host membrane ; Multi-pass membrane protein . Non-structural protein 7: Host cytoplasm, host perinuclear region . Non-structural protein 8: Host cytoplasm, host perinuclear region . Non-structural protein 9: Host cytoplasm, host perinuclear region . Non-structural protein 10: Host cytoplasm, host perinuclear region : P0C6U8
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72374.84

構造登録者

Baez-Santos, Y.M.,Mesecar, A. (登録日: 2014-01-28, 公開日: 2014-04-23, 最終更新日: 2023-11-15)

主引用文献

Baez-Santos, Y.M.,Barraza, S.J.,Wilson, M.W.,Agius, M.P.,Mielech, A.M.,Davis, N.M.,Baker, S.C.,Larsen, S.D.,Mesecar, A.D.
X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases.
J.Med.Chem., 57:2393-2412, 2014

PubMed Abstract: Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.

PubMed: 24568342
DOI: 10.1021/jm401712t

実験手法

X-RAY DIFFRACTION (2.1 Å)