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

Structural Bases of Norovirus RNA Dependent RNA Polymerase Inhibition by Novel Suramin-Related Compounds

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Free PMC article

Structural Bases of Norovirus RNA Dependent RNA Polymerase Inhibition by Novel Suramin-Related Compounds

Romina Croci et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

Competing Interests: Co-author Dr J. Rohayem is an employee of the company Riboxx GmbH (Germany) and this function does not lead to conflicts of interest and does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Suramin derivative 8 synthesis.
Total synthesis of Suramin derivative 8 from commercially available starting materials. The Suramin molecule (9) is also shown for comparison.
Figure 2
Figure 2. Superposition of hNV and mNV-RdRp/6 complex structures.
Superposition of the crystal structures of hNV-RdRp in cartoon (magenta) bound to 6 (yellow carbon atoms) in sticks, onto mNV-RdRp in cartoon (blue), bound to 6 (carbon atoms in green) in sticks. The suramin position (in sticks orange carbons) is obtained from superposition of pdb-id 3UR0 (Mastrangelo et al., 2012) (Figures created using PyMol (http://www.pymol.org)).
Figure 3
Figure 3. Interaction network of hNV and mNV-RdRp/6 complex.
A) Fragment of 6 (carbon atoms in yellow) bound to hNV-RdRp in cartoon (magenta). All the amino acids involved in interaction with the inhibitor molecule are shown in sticks (carbon atoms in magenta). B) 6 (carbon atoms in green) bound to mNV-RdRp in cartoon (blue). All the amino acids (carbon atoms in blue) involved in interaction with the molecule are shown in sticks. 2Fo-Fc electron density contoured at 1 sigma in blue grid. C) Superposition of hNV-RdRp and mNV-RdRp, showing the structures of 6 (carbon atoms in yellow/green, respectively) bound to hNV-RdRp and to mNV-RdRp (cartoon in magenta/blue, respectively). The interacting amino acids are shown in sticks (magenta/blue carbon atoms, respectively).

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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.
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