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

Author

Romina Croci, Margherita Pezzullo, Delia Tarantino, Mario Milani, Shwu-Chen Tsay, Radhakrishnan Sureshbabu, Yi-Jin Tsai, Eloise Mastrangelo, Jacques Rohayem, Martino Bolognesi, and Jih Ru Hwu

Subjects
Medicine, Science
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.

Published
2014
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2. Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds

Author

Yi-Jin Tsai, Eloise Mastrangelo, Martino Bolognesi, Radhakrishnan Sureshbabu, Shwu-Chen Tsay, Delia Tarantino, Margherita Pezzullo, Jih Ru Hwu, Romina Croci, Jacques Rohayem, and Mario Milani

Subjects
Protein Structure, Protein Conformation, Suramin, viruses, Biophysics, RNA-dependent RNA polymerase, lcsh:Medicine, Crystallography, X-Ray, Biochemistry, chemistry.chemical_compound, Mice, Structure-Activity Relationship, In vivo, RNA polymerase, Drug Discovery, Chemical Biology, medicine, Structure–activity relationship, Potency, Animals, Humans, Urea, Enzyme Inhibitors, Biomacromolecule-Ligand Interactions, lcsh:Science, IC50, Biology, Multidisciplinary, lcsh:R, Norovirus, Organic Chemistry, Proteins, RNA-Dependent RNA Polymerase, In vitro, Enzymes, Molecular Docking Simulation, Molecular Weight, Chemistry, chemistry, Small Molecules, Drug Design, Enzyme Structure, lcsh:Q, Sulfonic Acids, Medicinal Chemistry, medicine.drug, Research 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.

Published
2013

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