title: Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds.
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.
authors.affiliation: Department of BioSciences, University of Milano, Milano, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Croci
authors.affiliation: Department of BioSciences, University of Milano, Milano, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Pezzullo
authors.affiliation: Department of BioSciences, University of Milano, Milano, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Tarantino
authors.affiliation: Department of BioSciences, University of Milano, Milano, Italy; Istituto di Biofisica,CNR IBF, Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Milani
authors.affiliation: Department of Chemistry, National Central University, Jhongli, Taiwan.
authors.forename: Shwu-Chen
authors.initials: SC
authors.lastname: Tsay
authors.affiliation: Department of Chemistry and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Sureshbabu
authors.affiliation: Department of Chemistry and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yi-Jin
authors.initials: YJ
authors.lastname: Tsai
authors.affiliation: Department of BioSciences, University of Milano, Milano, Italy; Istituto di Biofisica,CNR IBF, Milano, Italy.
authors.forename: Eloise
authors.initials: E
authors.lastname: Mastrangelo
authors.affiliation: Riboxx GmbH, Pharmapark Radebeul, Radebeul, Germany; Institute of Virology, Dresden University of Technology, Dresden, Germany.
authors.forename: Jacques
authors.initials: J
authors.lastname: Rohayem
authors.affiliation: Department of BioSciences, University of Milano, Milano, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.affiliation: Department of Chemistry, National Central University, Jhongli, Taiwan; Department of Chemistry and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Jih Ru
authors.initials: JR
authors.lastname: Hwu
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D029322:Norovirus / Q000201:enzymology*; D011487:Protein Conformation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013498:Suramin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; D013498:Suramin; D014508:Urea; D012324:RNA-Dependent RNA Polymerase