8IHO

Crystal structures of SARS-CoV-2 papain-like protease in complex with covalent inhibitors

Summary for 8IHO

• Entry DOI: 10.2210/pdb8iho/pdb
• Descriptor: Papain-like protease nsp3, covalent inhibitor, ZINC ION (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 4
• Total formula weight: 72729.41

Authors

Wang, Q.,Hu, H.,Li, M.,Xu, Y. (deposition date: 2023-02-23, release date: 2024-01-03, Last modification date: 2024-11-20)

Primary citation

Wang, Q.,Chen, G.,He, J.,Li, J.,Xiong, M.,Su, H.,Li, M.,Hu, H.,Xu, Y.
Structure-Based Design of Potent Peptidomimetic Inhibitors Covalently Targeting SARS-CoV-2 Papain-like Protease.
Int J Mol Sci, 24:-, 2023

PubMed Abstract: The papain-like protease (PL) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PL. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC = 0.23 μM) and significant inhibition of SARS-CoV-2 PL in the HEK293T cells using a cell-based protease assay (EC = 3.61 μM). Moreover, an X-ray crystal structure of SARS-CoV-2 PL in complex with compound confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PL inhibitors and provide an attractive starting point for further optimization.

PubMed: 37239980
DOI: 10.3390/ijms24108633

Experimental method

X-RAY DIFFRACTION (2.55 Å)