9ZJ4

Crystal structure of SARS-CoV-2 3CL protease in complex with inhibitor IKR-I-45

This is a non-PDB format compatible entry.

Summary for 9ZJ4

• Entry DOI: 10.2210/pdb9zj4/pdb
• Descriptor: 3C-like proteinase, CHLORIDE ION, N~2~-[(2S,4S)-3-benzyl-4-methyl-2-oxo-1,3,2lambda~5~-oxazaphospholidin-2-yl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide, ... (4 entities in total)
• Functional Keywords: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34582.78

Authors

Ung, A.R.,Lovell, S.,Battaile, K.P.,Ilesinghe, I.K.R.S.,Groutas, W.C. (deposition date: 2025-12-04, release date: 2026-06-10)

Primary citation

Nguyen, H.N.,Ranasinghe, P.S.,Ilesinghe, I.K.R.S.,Dampalla, C.S.,Rathnayake, A.D.,Liska, Z.,Jesri, A.M.,Azmi, Z.,Nevonen, D.E.,Kim, Y.,Ung, A.R.,Taylor, K.E.,Cooper, A.,Liu, L.,Battaile, K.P.,Thurman, H.A.,Gusachenko, E.,Lovell, S.,Groutas, W.C.,Chang, K.O.
Structure-guided design of broad-spectrum inhibitors of coronaviral proteases embodying a 1,3,2-oxazaphospholidin-3-one scaffold as a versatile design element.
Eur.J.Med.Chem., 316:119002-119002, 2026

PubMed Abstract: Constant changes in SARS-CoV-2 in human populations as well as potential future spillovers from animal coronaviruses have provided the impetus for the development of additional direct-acting antivirals. We describe herein the discovery of a new class of broad-spectrum inhibitors of coronavirus 3C-like protease (3CLpro), a cysteine protease essential for viral replication and a validated drug target, that incorporate in their structure a 1,3,2-oxazaphospholidin-3-one scaffold. Inhibitors 1 and 2 potently inhibited SARS-CoV-2 3CLpro (IC = 0.34 and 0.23 μM) and MERS-CoV 3CLpro (IC = 0.12 and 0.09 μM), and displayed antiviral activity against SARS-CoV-2 (EC = 60 and 50 nM) with low cytotoxicity (CC > 100 μM). Importantly, several of the synthesized compounds inhibited recombinant human cathepsin L with IC values in the low nM to sub-nM range. Thus, the compounds can potentially exhibit high antiviral potency by abrogating viral entry via the inhibition of cathepsin L and viral replication by inhibition of 3CLpro. High resolution cocrystal structures were determined to elucidate the mechanism of action, identify the molecular determinants associated with binding, and to inform the optimization process.

PubMed: 42208369
DOI: 10.1016/j.ejmech.2026.119002

Experimental method

X-RAY DIFFRACTION (2.44 Å)