4NRT

Human Norovirus polymerase bound to Compound 6 (suramin derivative)

Summary for 4NRT

• Entry DOI: 10.2210/pdb4nrt/pdb
• Descriptor: hNV-RdRp, 4-({4-methyl-3-[(3-nitrobenzoyl)amino]benzoyl}amino)naphthalene-1,5-disulfonic acid (3 entities in total)
• Functional Keywords: rna dependent rna polymerase, viral protein-transcription inhibitor complex, viral protein/transcription inhibitor
• Biological source: Norwalk-like virus
• Total number of polymer chains: 1
• Total formula weight: 59243.32

Authors

Croci, R.,Pezzullo, M.,Tarantino, D.,Mastrangelo, E.,Milani, M.,Bolognesi, M. (deposition date: 2013-11-27, release date: 2014-10-15, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.022 Å)