9CYC

SARS-CoV-2 PLpro in complex with inhibitor WEHI-P2

これはPDB形式変換不可エントリーです。

9CYC の概要

• エントリーDOI: 10.2210/pdb9cyc/pdb
• 分子名称: Papain-like protease, (E)-1-[(3R)-1-cyclopentylpiperidin-3-yl]-N-methoxy-1-(6-methoxynaphthalen-2-yl)methanimine, ACETIC ACID, ... (5 entities in total)
• 機能のキーワード: sars cov-2, papain-like protease, covid19, inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73076.86

構造登録者

Calleja, D.J.,Lechtenberg, B.C.,Kuchel, N.W.,Devine, S.M.,Bader, S.M.,Doerflinger, M.,Mitchel, J.P.,Lessene, G.,Komander, D. (登録日: 2024-08-01, 公開日: 2025-04-09, 最終更新日: 2025-04-16)

主引用文献

M Bader, S.,Calleja, D.J.,Devine, S.M.,Kuchel, N.W.,Lu, B.G.C.,Wu, X.,Birkinshaw, R.W.,Bhandari, R.,Loi, K.,Volpe, R.,Khakham, Y.,Au, A.E.,Blackmore, T.R.,Mackiewicz, L.,Dayton, M.,Schaefer, J.,Scherer, L.,Stock, A.T.,Cooney, J.P.,Schoffer, K.,Maluenda, A.,Kleeman, E.A.,Davidson, K.C.,Allison, C.C.,Ebert, G.,Chen, G.,Katneni, K.,Klemm, T.A.,Nachbur, U.,Georgy, S.R.,Czabotar, P.E.,Hannan, A.J.,Putoczki, T.L.,Tanzer, M.,Pellegrini, M.,Lechtenberg, B.C.,Charman, S.A.,Call, M.J.,Mitchell, J.P.,Lowes, K.N.,Lessene, G.,Doerflinger, M.,Komander, D.
A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID.
Nat Commun, 16:2900-2900, 2025

PubMed Abstract: The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has highlighted the vulnerability of a globally connected population to zoonotic viruses. The FDA-approved coronavirus antiviral Paxlovid targets the essential SARS-CoV-2 main protease, Mpro. Whilst effective in the acute phase of a COVID infection, Paxlovid cannot be used by all patients, can lead to viral recurrence, and does not protect against post-acute sequelae of COVID-19 (PASC), commonly known as long COVID, an emerging significant health burden that remains poorly understood and untreated. Alternative antivirals that are addressing broader patient needs are urgently required. We here report our drug discovery efforts to target PLpro, a further essential coronaviral protease, for which we report a novel chemical scaffold that targets SARS-CoV-2 PLpro with low nanomolar activity, and which exhibits activity against PLpro of other pathogenic coronaviruses. Our lead compound shows excellent in vivo efficacy in a mouse model of severe acute disease. Importantly, our mouse model recapitulates long-term pathologies matching closely those seen in PASC patients. Our lead compound offers protection against a range of PASC symptoms in this model, prevents lung pathology and reduces brain dysfunction. This provides proof-of-principle that PLpro inhibition may have clinical relevance for PASC prevention and treatment going forward.

PubMed: 40180914
DOI: 10.1038/s41467-025-57905-4

実験手法

X-RAY DIFFRACTION (2.01 Å)