9SAM

Crystal structure of SARS-CoV-2 NSP14 in complex with compound 26

This is a non-PDB format compatible entry.

Summary for 9SAM

• Entry DOI: 10.2210/pdb9sam/pdb
• Descriptor: Guanine-N7 methyltransferase nsp14, ZINC ION, IMIDAZOLE, ... (5 entities in total)
• Functional Keywords: nsp14, sars-cov-2 nsp14, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 120651.52

Authors

Georgiou, I.,Robinson, C.,OByrne, S.,Matsuda, A.,Grygier, P.,Smith, C.,ONeill, S.,Ahmad, S.,Post, J.,Groenewold, G.J.M.,Urakova, N.,Wanningen, P.,Kresik, L.,Plewka, J.,Delpal, A.,See, K.,Eadsforth, T.,Paul, M.,Lis, K.,Decroly, E.,Singh Saikatendu, K.,Chang, E.,Snijder, E.J.,Czarna, A.,Pyrc, K.,Scott, D.,Gilbert, I. (deposition date: 2025-08-07, release date: 2026-01-21)

Primary citation

Georgiou, I.,Robinson, C.,O'Byrne, S.N.,Matsuda, A.,Grygier, P.,Smith, C.D.,O'Neill, S.,Ahmad, S.A.,Norval, S.,Post, J.M.,Groenewold, M.,Urakova, N.,Wanningen, P.,Kresik, L.,Plewka, J.,Delpal, A.,See, K.,Eadsforth, T.,Wierzbicka, K.,Decroly, E.,Saikatendu, K.S.,Chang, E.,Snijder, E.J.,Pyrc, K.,Czarna, A.,Scott, D.E.,Gilbert, I.H.
Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase.
Rsc Med Chem, 2026

PubMed Abstract: SARS-CoV-2 non-structural protein 14 (nsp14) is essential for viral mRNA cap guanine-N7 methylation and represents a promising but underexplored antiviral target. Herein we describe a structure-guided campaign based on a hit from a focussed SAM mimetic library. Systematic SAR exploration guided by six X-ray co-crystal structures in complex with SARS-CoV-2 led to compound 26, a bi-substrate inhibitor that bridges the SAM and RNA cap binding sites. Compound 26 achieved nanomolar potency against nsp14 from SARS-CoV-2 (IC = 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity.

PubMed: 41502823
DOI: 10.1039/d5md00896d

Experimental method

X-RAY DIFFRACTION (2.54 Å)