7D3I

Crystal structure of SARS-CoV-2 main protease in complex with MI-23

Summary for 7D3I

• Entry DOI: 10.2210/pdb7d3i/pdb
• Descriptor: 3C-like proteinase, (3~{S},3~{a}~{S},6~{a}~{R})-2-[3-[3,5-bis(fluoranyl)phenyl]propanoyl]-~{N}-[(2~{S})-1-oxidanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]-3,3~{a},4,5,6,6~{a}-hexahydro-1~{H}-cyclopenta[c]pyrrole-3-carboxamide, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• Functional Keywords: coronavirus, protease, inhibitor, complex, viral protein., viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 34409.19

Authors

Zeng, R.,Li, Y.S.,Qiao, J.X.,Wang, Y.F.,Yang, S.Y.,Lei, J. (deposition date: 2020-09-19, release date: 2020-10-07, Last modification date: 2023-11-29)

Primary citation

Qiao, J.,Li, Y.S.,Zeng, R.,Liu, F.L.,Luo, R.H.,Huang, C.,Wang, Y.F.,Zhang, J.,Quan, B.,Shen, C.,Mao, X.,Liu, X.,Sun, W.,Yang, W.,Ni, X.,Wang, K.,Xu, L.,Duan, Z.L.,Zou, Q.C.,Zhang, H.L.,Qu, W.,Long, Y.H.,Li, M.H.,Yang, R.C.,Liu, X.,You, J.,Zhou, Y.,Yao, R.,Li, W.P.,Liu, J.M.,Chen, P.,Liu, Y.,Lin, G.F.,Yang, X.,Zou, J.,Li, L.,Hu, Y.,Lu, G.W.,Li, W.M.,Wei, Y.Q.,Zheng, Y.T.,Lei, J.,Yang, S.
SARS-CoV-2 M pro inhibitors with antiviral activity in a transgenic mouse model.
Science, 371:1374-1378, 2021

PubMed Abstract: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (M) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing M inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 M activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of M in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

PubMed: 33602867
DOI: 10.1126/science.abf1611

Experimental method

X-RAY DIFFRACTION (2.004 Å)