7TIZ

Crystal structure of SARS-CoV-2 3CL in complex with inhibitor NK01-63

Summary for 7TIZ

• Entry DOI: 10.2210/pdb7tiz/pdb
• Descriptor: 3C-like proteinase nsp5, (1S,2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]-2-{[N-({[3-(trifluoromethyl)phenyl]methoxy}carbonyl)-L-leucyl]amino}propane-1-sulfonic acid, SODIUM ION, ... (6 entities in total)
• Functional Keywords: viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34522.24

Authors

Forouhar, F.,Liu, H.,Iketani, S.,Zack, A.,Khanizeman, N.,Bednarova, E.,Fowler, B.,Hong, S.J.,Mohri, H.,Nair, M.S.,Huang, Y.,Tay, N.E.S.,Lee, S.,Karan, C.,Resnick, S.J.,Quinn, C.,Li, W.,Shion, H.,Jurtschenko, C.,Lauber, M.A.,McDonald, T.,Stokes, M.E.,Hurst, B.,Rovis, T.,Chavez, A.,Ho, D.D.,Stockwell, B.R. (deposition date: 2022-01-14, release date: 2022-05-04, Last modification date: 2024-10-16)

Primary citation

Liu, H.,Iketani, S.,Zask, A.,Khanizeman, N.,Bednarova, E.,Forouhar, F.,Fowler, B.,Hong, S.J.,Mohri, H.,Nair, M.S.,Huang, Y.,Tay, N.E.S.,Lee, S.,Karan, C.,Resnick, S.J.,Quinn, C.,Li, W.,Shion, H.,Xia, X.,Daniels, J.D.,Bartolo-Cruz, M.,Farina, M.,Rajbhandari, P.,Jurtschenko, C.,Lauber, M.A.,McDonald, T.,Stokes, M.E.,Hurst, B.L.,Rovis, T.,Chavez, A.,Ho, D.D.,Stockwell, B.R.
Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.
Nat Commun, 13:1891-1891, 2022

PubMed Abstract: The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

PubMed: 35393402
DOI: 10.1038/s41467-022-29413-2

Experimental method

X-RAY DIFFRACTION (1.55 Å)