Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds

PLoS One. 2014 Mar 12;9(3):e91765. doi: 10.1371/journal.pone.0091765. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Weight
  • Norovirus / enzymology*
  • Protein Conformation
  • RNA Replicase / antagonists & inhibitors*
  • RNA Replicase / chemistry
  • RNA Replicase / metabolism
  • Structure-Activity Relationship
  • Sulfonic Acids / chemical synthesis
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / metabolism
  • Sulfonic Acids / pharmacology
  • Suramin / chemical synthesis
  • Suramin / chemistry*
  • Suramin / metabolism
  • Suramin / pharmacology*
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / metabolism
  • Urea / pharmacology

Substances

  • Enzyme Inhibitors
  • Sulfonic Acids
  • Suramin
  • Urea
  • RNA Replicase

Grant support

National Science Council (NSC 102-2923-I-008-001), Ministry of Education of the R.O.C., Taiwan (grants nos. 102N2011E1 and 102N2018E1), and National Central University (102G918). The work at University of Milano and CNR (Milano, Italy) and at Riboxx GmbH (Dresden Germany) was supported by the European Commission SILVER project, within the 7th Framework Program Cooperation Project Grant Agreement No. 2606444. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.