13OC

PanDDA analysis group deposition -- Crystal structure of PLpro-C111S in complex with Fr13508

Summary for 13OC

• Entry DOI: 10.2210/pdb13oc/pdb
• Group deposition: Crystallographic fragment screening of SARS-CoV-2 PLpro-C111S mutant (G_1002354)
• Descriptor: Papain-like protease nsp3, ZINC ION, MALONATE ION, ... (5 entities in total)
• Functional Keywords: plpro, sars-cov-2, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 40206.79

Authors

Wang, W.,Hu, L.,Xu, Q.,Zu, Z.,Lu, M.,Zu, H.,Hu, T.,Zu, S.,Wu, Q.,Yu, F. (deposition date: 2025-09-17, release date: 2026-02-18)

Primary citation

Wang, W.W.,Huang, L.Q.,Xu, Q.,Zhu, Z.M.,Li, M.,Zhou, H.,Han, T.L.,Zheng, S.H.,Li, J.,Wang, Q.S.,Yu, F.
Crystallographic fragment screening discovers novel micromolar active inhibitors and druggable hotspots of SARS-CoV-2 PL pro.
Int.J.Biol.Macromol., 347:150689-150689, 2026

PubMed Abstract: The COVID-19 pandemic has highlighted the need to develop broad-spectrum antiviral therapeutics targeting rapidly evolving coronaviruses. This research focuses on SARS-CoV-2 PL, a conserved viral protease that plays dual roles in viral polyprotein processing and host immune suppression. Using an integrated fragment-based drug discovery (FBDD) approach that combines high-throughput X-ray crystallography and biochemical assays, we systematically screened a diverse library of 800 fragment compounds. Structural characterization identified 129 validated binders occupying 12 distinct binding sites on PL. Remarkably, two fragments demonstrated potent micromolar inhibitory activity. Fr12895 inhibited SARS-CoV-2 PL protease activity (IC = 8.013 μM), as measured using the fluorogenic substrate RLRGG-AMC, while Fr12338 showed inhibition against PL deISGylase activity (IC = 4.5 μM), as determined with the substrate Ac-ISG15prox-Rh110MP. This provides a case for directly obtaining micromolar-active compounds through crystallographic fragment screening of a small number of random compounds. Detailed structural analysis revealed these fragments engage key functional regions including the blocking loop 2 (BL2) and ubiquitin/ISG15 binding interface through extensive hydrogen-bond networks and hydrophobic interactions. Our study reveals novel micromolar active inhibitors and druggable sites of SARS-CoV-2 PL by crystallographic fragment screening, provides crucial scaffold and a structural roadmap for developing broad-spectrum antivirals against coronaviruses.

PubMed: 41638277
DOI: 10.1016/j.ijbiomac.2026.150689

Experimental method

X-RAY DIFFRACTION (1.81 Å)