8A4T

crystal structures of diastereomer (S,S,S)-13b (13b-K) in complex with the SARS-CoV-2 Mpro

Summary for 8A4T

• Entry DOI: 10.2210/pdb8a4t/pdb
• Related: 8A4Q
• Descriptor: 3C-like proteinase nsp5, ~{tert}-butyl ~{N}-[1-[(2~{S})-3-cyclopropyl-1-oxidanylidene-1-[[(2~{S},3~{R})-3-oxidanyl-4-oxidanylidene-1-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]-4-[(phenylmethyl)amino]butan-2-yl]amino]propan-2-yl]-2-oxidanylidene-pyridin-3-yl]carbamate, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: zhang, l., antiviral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68621.66

Authors

Ibrahim, M.,Hilgenfeld, R.,Zhang, L. (deposition date: 2022-06-13, release date: 2022-10-12, Last modification date: 2024-02-07)

Primary citation

Cooper, M.S.,Zhang, L.,Ibrahim, M.,Zhang, K.,Sun, X.,Roske, J.,Gohl, M.,Bronstrup, M.,Cowell, J.K.,Sauerhering, L.,Becker, S.,Vangeel, L.,Jochmans, D.,Neyts, J.,Rox, K.,Marsh, G.P.,Maple, H.J.,Hilgenfeld, R.
Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease.
J.Med.Chem., 65:13328-13342, 2022

PubMed Abstract: SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (M, 3CL) of SARS-CoV-2 is a key enzyme that processes polyproteins translated from the viral RNA. M is therefore an attractive target for the design of inhibitors that block viral replication. We report the diastereomeric resolution of the previously designed SARS-CoV-2 M α-ketoamide inhibitor . The pure ()-diastereomer, , displays an IC of 120 nM against the M and EC values of 0.8-3.4 μM for antiviral activity in different cell types. Crystal structures have been elucidated for the M complexes with each of the major diastereomers, the active ()-13b (), and the nearly inactive ()-13b (); results for the latter reveal a novel binding mode. Pharmacokinetic studies show good levels of after inhalative as well as after peroral administration. The active inhibitor () is a promising candidate for further development as an antiviral treatment for COVID-19.

PubMed: 36179320
DOI: 10.1021/acs.jmedchem.2c01131

Experimental method

X-RAY DIFFRACTION (2.5 Å)