Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds.
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 pharma...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3951423?pdf=render |
| _version_ | 1811310904087674880 |
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| author | Romina Croci Margherita Pezzullo Delia Tarantino Mario Milani Shwu-Chen Tsay Radhakrishnan Sureshbabu Yi-Jin Tsai Eloise Mastrangelo Jacques Rohayem Martino Bolognesi Jih Ru Hwu |
| author_facet | Romina Croci Margherita Pezzullo Delia Tarantino Mario Milani Shwu-Chen Tsay Radhakrishnan Sureshbabu Yi-Jin Tsai Eloise Mastrangelo Jacques Rohayem Martino Bolognesi Jih Ru Hwu |
| author_sort | Romina Croci |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T10:08:21Z |
| format | Article |
| id | doaj.art-3bb15fd0144147289af16ceed90b73e6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T10:08:21Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3bb15fd0144147289af16ceed90b73e62022-12-22T02:51:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e9176510.1371/journal.pone.0091765Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds.Romina CrociMargherita PezzulloDelia TarantinoMario MilaniShwu-Chen TsayRadhakrishnan SureshbabuYi-Jin TsaiEloise MastrangeloJacques RohayemMartino BolognesiJih Ru HwuNoroviruses (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.http://europepmc.org/articles/PMC3951423?pdf=render |
| spellingShingle | Romina Croci Margherita Pezzullo Delia Tarantino Mario Milani Shwu-Chen Tsay Radhakrishnan Sureshbabu Yi-Jin Tsai Eloise Mastrangelo Jacques Rohayem Martino Bolognesi Jih Ru Hwu Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds. PLoS ONE |
| title | Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds. |
| title_full | Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds. |
| title_fullStr | Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds. |
| title_full_unstemmed | Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds. |
| title_short | Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds. |
| title_sort | structural bases of norovirus rna dependent rna polymerase inhibition by novel suramin related compounds |
| url | http://europepmc.org/articles/PMC3951423?pdf=render |
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