8YX5

Crystal Structure of SARS CoV-2 Papain-like Protease PLpro-C111S in Complex with GZNL-P35

これはPDB形式変換不可エントリーです。

8YX5 の概要

• エントリーDOI: 10.2210/pdb8yx5/pdb
• 分子名称: Papain-like protease nsp3, 5-[(1~{R},5~{S})-3,6-diazabicyclo[3.1.1]heptan-3-yl]-2-methyl-~{N}-[1-(1-methyl-2-oxidanylidene-benzo[cd]indol-6-yl)cyclopropyl]benzamide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: sars cov-2, papain-like proteinase, nsp3, hydrolase
• 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: 72960.08

構造登録者

Lu, Y.,Shang, J. (登録日: 2024-04-02, 公開日: 2024-12-04)

主引用文献

Lu, Y.,Yang, Q.,Ran, T.,Zhang, G.,Li, W.,Zhou, P.,Tang, J.,Dai, M.,Zhong, J.,Chen, H.,He, P.,Zhou, A.,Xue, B.,Chen, J.,Zhang, J.,Yang, S.,Wu, K.,Wu, X.,Tang, M.,Zhang, W.K.,Guo, D.,Chen, X.,Chen, H.,Shang, J.
Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19.
Nat Commun, 15:10169-10169, 2024

PubMed Abstract: The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CL), and papain-like protease (PL) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CL inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CL from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discover a series of novel potent non-covalent PL inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PL with lead compounds reveal that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor's potency. The lead compound GZNL-P36 not only inhibits SARS-CoV-2 and its variants at the cellular level with EC ranging from 58.2 nM to 306.2 nM, but also inhibits HCoV-NL63 and HCoV-229E with EC of 81.6 nM and 2.66 μM, respectively. Oral administration of the GZNL-P36 results in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PL inhibitors represent a promising SARS-CoV-2 therapy.

PubMed: 39580525
DOI: 10.1038/s41467-024-54462-0

実験手法

X-RAY DIFFRACTION (1.74 Å)