8CYU

Crystal structure of SARS-CoV-2 Mpro with compound C5

8CYU の概要

• エントリーDOI: 10.2210/pdb8cyu/pdb
• 関連するPDBエントリー: 8CYP 8CYQ
• 分子名称: 3C-like proteinase, N-[(4-chlorothiophen-2-yl)methyl]-N-[4-(dimethylamino)phenyl]-2-(isoquinolin-4-yl)acetamide (3 entities in total)
• 機能のキーワード: covid-19, sars-cov-2, protease, inhibitor, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 137046.06

構造登録者

Worrall, L.J.,Lee, J.,Strynadka, N.C.J. (登録日: 2022-05-24, 公開日: 2023-08-30)

主引用文献

Perez-Vargas, J.,Worrall, L.J.,Olmstead, A.D.,Ton, A.T.,Lee, J.,Villanueva, I.,Thompson, C.A.H.,Dudek, S.,Ennis, S.,Smith, J.R.,Shapira, T.,De Guzman, J.,Gang, S.,Ban, F.,Vuckovic, M.,Bielecki, M.,Kovacic, S.,Kenward, C.,Hong, C.Y.,Gordon, D.G.,Levett, P.N.,Krajden, M.,Leduc, R.,Boudreault, P.L.,Niikura, M.,Paetzel, M.,Young, R.N.,Cherkasov, A.,Strynadka, N.C.J.,Jean, F.
A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants.
Emerg Microbes Infect, 12:2246594-2246594, 2023

PubMed Abstract: Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (). Our lead direct-acting antiviral (DAA), , is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, has median effective concentrations of 30-50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs () and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.

PubMed: 37555275
DOI: 10.1080/22221751.2023.2246594

実験手法

X-RAY DIFFRACTION (1.8 Å)