7SDA

Structure of the SARS-CoV-2 main protease in complex with inhibitor MPI49

Summary for 7SDA

• Entry DOI: 10.2210/pdb7sda/pdb
• Descriptor: 3C-like proteinase, N-[(2S)-1-({(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)-4,4-dimethyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide (3 entities in total)
• Functional Keywords: main protease, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus)
• Total number of polymer chains: 1
• Total formula weight: 34226.06

Authors

Yang, K.S.,Liu, W.R. (deposition date: 2021-09-29, release date: 2022-11-09, Last modification date: 2024-03-20)

Primary citation

Geng, Z.Z.,Atla, S.,Shaabani, N.,Vulupala, V.,Yang, K.S.,Alugubelli, Y.R.,Khatua, K.,Chen, P.H.,Xiao, J.,Blankenship, L.R.,Ma, X.R.,Vatansever, E.C.,Cho, C.D.,Ma, Y.,Allen, R.,Ji, H.,Xu, S.,Liu, W.R.
A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease.
J.Med.Chem., 66:11040-11055, 2023

PubMed Abstract: SARS-CoV-2, the COVID-19 pathogen, relies on its main protease (M) for replication and pathogenesis. M is a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as M inhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 dipeptidyl M inhibitors and characterized them on enzymatic inhibition potency, structures of their complexes with M, cellular M inhibition potency, antiviral potency, cytotoxicity, and metabolic stability. Our results indicated that M has a flexible S2 pocket to accommodate inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as ()-2-azaspiro [4,4]nonane-3-carboxylate and ()-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics. One compound, MPI60, containing a P2 ()-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and high metabolic stability.

PubMed: 37561993
DOI: 10.1021/acs.jmedchem.3c00221

Experimental method

X-RAY DIFFRACTION (1.85 Å)