8DOX

Crystal structure of SARS-CoV-2 main protease in complex with an inhibitor TKB-245

Summary for 8DOX

• Entry DOI: 10.2210/pdb8dox/pdb
• Descriptor: 3C-like proteinase nsp5, (1R,2S,5S)-N-{(1S,2S)-1-(4-fluoro-1,3-benzothiazol-2-yl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: sars-cov-2 main protease, 3c-like proteinase, viral protein, sars-cov-2, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34140.90

Authors

Bulut, H.,Hayashi, H.,Tsuji, K.,Kuwata, N.,Das, D.,Tamamura, H.,Mitsuya, H. (deposition date: 2022-07-14, release date: 2022-09-21, Last modification date: 2024-10-23)

Primary citation

Higashi-Kuwata, N.,Tsuji, K.,Hayashi, H.,Bulut, H.,Kiso, M.,Imai, M.,Ogata-Aoki, H.,Ishii, T.,Kobayakawa, T.,Nakano, K.,Takamune, N.,Kishimoto, N.,Hattori, S.I.,Das, D.,Uemura, Y.,Shimizu, Y.,Aoki, M.,Hasegawa, K.,Suzuki, S.,Nishiyama, A.,Saruwatari, J.,Shimizu, Y.,Sukenaga, Y.,Takamatsu, Y.,Tsuchiya, K.,Maeda, K.,Yoshimura, K.,Iida, S.,Ozono, S.,Suzuki, T.,Okamura, T.,Misumi, S.,Kawaoka, Y.,Tamamura, H.,Mitsuya, H.
Identification of SARS-CoV-2 M pro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2.
Nat Commun, 14:1076-1076, 2023

PubMed Abstract: COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (M) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer M, apparently promoting M dimerization. X-ray crystallographic analysis shows that both compounds bind to M's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.

PubMed: 36841831
DOI: 10.1038/s41467-023-36729-0

Experimental method

X-RAY DIFFRACTION (1.46 Å)