9EOR

SARS-CoV2 major protease in complex with a covalent inhibitor SLL12.

これはPDB形式変換不可エントリーです。

9EOR の概要

• エントリーDOI: 10.2210/pdb9eor/pdb
• 関連するPDBエントリー: 9EO6
• 分子名称: 3C-like proteinase nsp5, Inhibitor SLL12, POTASSIUM ION, ... (4 entities in total)
• 機能のキーワード: inhibitor complex, antiviral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 206975.37

構造登録者

Moche, M.,Lennerstrand, J.,Nyman, T.,Strandback, E.,Akaberi, D. (登録日: 2024-03-15, 公開日: 2024-09-04, 最終更新日: 2024-10-16)

主引用文献

Akaberi, D.,Pourghasemi Lati, M.,Krambrich, J.,Berger, J.,Neilsen, G.,Strandback, E.,Turunen, S.P.,Wannberg, J.,Gullberg, H.,Moche, M.,Chinthakindi, P.K.,Nyman, T.,Sarafianos, S.G.,Sandstrom, A.,Jarhult, J.D.,Sandberg, K.,Lundkvist, A.,Verho, O.,Lennerstrand, J.
Identification of novel and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries.
Antimicrob.Agents Chemother., 68:e0090924-e0090924, 2024

PubMed Abstract: screening of large compound libraries with automated high-throughput screening is expensive and time-consuming and requires dedicated infrastructures. Conversely, the selection of DNA-encoded chemical libraries (DECLs) can be rapidly performed with routine equipment available in most laboratories. In this study, we identified novel inhibitors of SARS-CoV-2 main protease (M) through the affinity-based selection of the DELopen library (open access for academics), containing 4.2 billion compounds. The identified inhibitors were peptide-like compounds containing an N-terminal electrophilic group able to form a covalent bond with the nucleophilic Cys145 of M, as confirmed by x-ray crystallography. This DECL selection campaign enabled the discovery of the unoptimized compound SLL11 (IC = 30 nM), proving that the rapid exploration of large chemical spaces enabled by DECL technology allows for the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. As demonstrated further by x-ray crystallography, SLL11 was found to adopt a highly unique U-shaped binding conformation, which allows the N-terminal electrophilic group to loop back to the S1' subsite while the C-terminal amino acid sits in the S1 subsite. MP1, a close analog of SLL11, showed antiviral activity against SARS-CoV-2 in the low micromolar range when tested in Caco-2 and Calu-3 (EC = 2.3 µM) cell lines. As peptide-like compounds can suffer from low cell permeability and metabolic stability, the cyclization of the compounds will be explored in the future to improve their antiviral activity.

PubMed: 39194208
DOI: 10.1128/aac.00909-24

実験手法

X-RAY DIFFRACTION (2.25 Å)