8DOY

Crystal structure of SARS-CoV-2 main protease in complex with an inhibitor TKB-198

Summary for 8DOY

• Entry DOI: 10.2210/pdb8doy/pdb
• Descriptor: 3C-like proteinase nsp5, PENTAETHYLENE GLYCOL, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (7 entities in total)
• Functional Keywords: 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: 2
• Total formula weight: 68637.31

Authors

Bulut, H.,Hayashi, H.,Tsuji, K.,Kuwata, N.,Das, D.,Tamamura, H.,Mitsuya, H. (deposition date: 2022-07-14, release date: 2022-08-24, Last modification date: 2024-10-09)

Primary citation

Tsuji, K.,Ishii, T.,Kobayakawa, T.,Higashi-Kuwata, N.,Azuma, C.,Nakayama, M.,Onishi, T.,Nakano, H.,Wada, N.,Hori, M.,Shinohara, K.,Miura, Y.,Kawada, T.,Hayashi, H.,Hattori, S.I.,Bulut, H.,Das, D.,Takamune, N.,Kishimoto, N.,Saruwatari, J.,Okamura, T.,Nakano, K.,Misumi, S.,Mitsuya, H.,Tamamura, H.
Potent and biostable inhibitors of the main protease of SARS-CoV-2.
Iscience, 25:105365-105365, 2022

PubMed Abstract: Potent and biostable inhibitors of the main protease (M) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of M and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound is highly potent and blocks SARS-CoV-2 infection without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds ( and ), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds and its biostable derivative are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

PubMed: 36338434
DOI: 10.1016/j.isci.2022.105365

Experimental method

X-RAY DIFFRACTION (1.59 Å)