@article{Georgiou_I-2026_221638,
title = {Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase},
author = {Georgiou, I. and Robinson, C. and O'Byrne, S. and Matsuda, A. and Grygier, P. and Smith, C. and O'Neill, S. and Ahmad, S. and Norval, S. and Post, J. and Groenewold, G. and Urakova, N. and Wanningen, P. and Kresik, L. and Plewka, J. and Delpal, A. and See, K. and Eadsforth, T. and Wierzbicka, K. and Decroly, E. and Saikatendu, K. and Chang, E. and Snijder, E. and Pyrć, K. and Czarna, A. and Scott, D. and Gilbert, I.},
month = {jan},
year = {2026},
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 (IC₅₀ = 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.},
journal = {RSC Medicinal Chemistry},
publisher = {Royal Society of Chemistry},
url = {https://doi.org/10.1039/d5md00896d},
}
