9SAM

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

これはPDB形式変換不可エントリーです。

9SAM の概要

• エントリーDOI: 10.2210/pdb9sam/pdb
• 分子名称: Guanine-N7 methyltransferase nsp14, ZINC ION, IMIDAZOLE, ... (5 entities in total)
• 機能のキーワード: nsp14, sars-cov-2 nsp14, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 120651.52

構造登録者

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. (登録日: 2025-08-07, 公開日: 2026-01-21)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.54 Å)