8TV6
SARS-CoV-2 Mac1 in complex with MDOLL-0169
Summary for 8TV6
| Entry DOI | 10.2210/pdb8tv6/pdb |
| Descriptor | Papain-like protease nsp3, DI(HYDROXYETHYL)ETHER, (1R,6R)-6-{[3-(methoxycarbonyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-2-yl]carbamoyl}cyclohex-3-ene-1-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | hydrolase, macrodomain, inhibitor, covid-19, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, 2019-nCoV, COVID-19 virus) |
| Total number of polymer chains | 2 |
| Total formula weight | 37555.77 |
| Authors | Wazir, S.,Maksimainen, M.,Lehtio, L. (deposition date: 2023-08-17, release date: 2024-04-17, Last modification date: 2024-05-08) |
| Primary citation | Wazir, S.,Parviainen, T.A.O.,Pfannenstiel, J.J.,Duong, M.T.H.,Cluff, D.,Sowa, S.T.,Galera-Prat, A.,Ferraris, D.,Maksimainen, M.M.,Fehr, A.R.,Heiskanen, J.P.,Lehtio, L. Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target. J.Med.Chem., 67:6519-6536, 2024 Cited by PubMed Abstract: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound (MDOLL-0229) had an IC of 2.1 μM and was selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human proteins. The improved potency allowed testing of its effect on virus replication, and indeed, inhibited replication of both murine hepatitis virus (MHV) prototypes CoV and SARS-CoV-2. Sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of . Compound is the first Mac1-targeted small molecule demonstrated to inhibit coronavirus replication in a cell model. PubMed: 38592023DOI: 10.1021/acs.jmedchem.3c02451 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.74 Å) |
Structure validation
Download full validation report
