8E5X

Crystal structure of SARS-CoV-2 3CL protease in complex with a dimethyl sulfinyl benzene inhibitor

8E5X の概要

• エントリーDOI: 10.2210/pdb8e5x/pdb
• 分子名称: 3C-like proteinase, (2~{S})-2-[[(2~{S})-4-methyl-2-[[2-methyl-2-[oxidanyl(phenyl)-$l^{3}-sulfanyl]propoxy]carbonylamino]pentanoyl]amino]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propane-1-sulfonic acid, N~2~-(ethoxycarbonyl)-N-{(1S,2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-1-sulfanylpropan-2-yl}-L-leucinamide, ... (5 entities in total)
• 機能のキーワード: hydrolase, viral protein-inhibitor complex, viral protein/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: 70634.62

構造登録者

Lovell, S.,Machen, A.J.,Battaile, K.P.,Dampalla, C.S.,Groutas, W.C. (登録日: 2022-08-22, 公開日: 2022-09-07, 最終更新日: 2024-10-23)

主引用文献

Dampalla, C.S.,Miller, M.J.,Kim, Y.,Zabiegala, A.,Nguyen, H.N.,Madden, T.K.,Thurman, H.A.,Machen, A.J.,Cooper, A.,Liu, L.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV).
Eur.J.Med.Chem., 254:115376-115376, 2023

PubMed Abstract: The high morbidity and mortality associated with SARS-CoV-2 infection, the etiological agent of COVID-19, has had a major impact on global public health. Significant progress has been made in the development of an array of vaccines and biologics, however, the emergence of SARS-CoV-2 variants and breakthrough infections are an ongoing major concern. Furthermore, there is an existing paucity of small-molecule host and virus-directed therapeutics and prophylactics that can be used to counter the spread of SARS-CoV-2, and any emerging and re-emerging coronaviruses. We describe herein our efforts to address this urgent need by focusing on the structure-guided design of potent broad-spectrum inhibitors of SARS-CoV-2 3C-like protease (3CL or Main protease), an enzyme essential for viral replication. The inhibitors exploit the directional effects associated with the presence of a gem-dimethyl group that allow the inhibitors to optimally interact with the S4 subsite of the enzyme. Several compounds were found to potently inhibit SARS-CoV-2 and MERS-CoV 3CL proteases in biochemical and cell-based assays. Specifically, the EC50 values of aldehyde 1c and its corresponding bisulfite adduct 1d against SARS-CoV-2 were found to be 12 and 10 nM, respectively, and their CC50 values were >50 μM. Furthermore, deuteration of these compounds yielded compounds 2c/2d with EC50 values 11 and 12 nM, respectively. Replacement of the aldehyde warhead with a nitrile (CN) or an α-ketoamide warhead or its corresponding bisulfite adduct yielded compounds 1g, 1eand1f with EC50 values 60, 50 and 70 nM, respectively. High-resolution cocrystal structures have identified the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and, furthermore, have illuminated the mechanism of action of the inhibitors. Overall, the high Safety Index (SI) (SI=CC50/EC50) displayed by these compounds suggests that they are well-suited to conducting further preclinical studies.

PubMed: 37080108
DOI: 10.1016/j.ejmech.2023.115376

実験手法

X-RAY DIFFRACTION (1.7 Å)