4NRT

Human Norovirus polymerase bound to Compound 6 (suramin derivative)

4NRT の概要

• エントリーDOI: 10.2210/pdb4nrt/pdb
• 分子名称: hNV-RdRp, 4-({4-methyl-3-[(3-nitrobenzoyl)amino]benzoyl}amino)naphthalene-1,5-disulfonic acid (3 entities in total)
• 機能のキーワード: rna dependent rna polymerase, viral protein-transcription inhibitor complex, viral protein/transcription inhibitor
• 由来する生物種: Norwalk-like virus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 59243.32

構造登録者

Croci, R.,Pezzullo, M.,Tarantino, D.,Mastrangelo, E.,Milani, M.,Bolognesi, M. (登録日: 2013-11-27, 公開日: 2014-10-15, 最終更新日: 2023-09-20)

主引用文献

Croci, R.,Pezzullo, M.,Tarantino, D.,Milani, M.,Tsay, S.C.,Sureshbabu, R.,Tsai, Y.J.,Mastrangelo, E.,Rohayem, J.,Bolognesi, M.,Hwu, J.R.
Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds.
Plos One, 9:e91765-e91765, 2014

PubMed Abstract: Noroviruses (NV) are +ssRNA viruses responsible for severe gastroenteritis; no effective vaccines/antivirals are currently available. We previously identified Suramin (9) as a potent inhibitor of NV-RNA dependent RNA polymerase (NV-RdRp). Despite significant in vitro activities versus several pharmacological targets, Suramin clinical use is hampered by pharmacokinetics/toxicity problems. To improve Suramin access to NV-RdRp in vivo, a Suramin-derivative, 8, devoid of two sulphonate groups, was synthesized, achieving significant anti-human-NV-RdRp activity (IC50 = 28 nM); the compound inhibits also murine NV (mNV) RdRp. The synthesis process led to the isolation/characterization of lower molecular weight intermediates (3-7) hosting only one sulphonate head. The crystal structures of both hNV/mNV-RdRps in complex with 6, were analyzed, providing new knowledge on the interactions that a small fragment can establish with NV-RdRps, and establishing a platform for structure-guided optimization of potency, selectivity and drugability.

PubMed: 24622391
DOI: 10.1371/journal.pone.0091765

実験手法

X-RAY DIFFRACTION (2.022 Å)