More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules.
Enterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Ana...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2014
|
| _version_ | 1797057240677482496 |
|---|---|
| author | De Colibus, L Wang, X Spyrou, J Kelly, J Ren, J Grimes, J Puerstinger, G Stonehouse, N Walter, T Hu, Z Wang, J Li, X Peng, W Rowlands, D Fry, E Rao, Z Stuart, D |
| author_facet | De Colibus, L Wang, X Spyrou, J Kelly, J Ren, J Grimes, J Puerstinger, G Stonehouse, N Walter, T Hu, Z Wang, J Li, X Peng, W Rowlands, D Fry, E Rao, Z Stuart, D |
| author_sort | De Colibus, L |
| collection | OXFORD |
| description | Enterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics-enhanced ligand docking and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (with IC50 of 25 pM) is an order of magnitude more potent than the best previously reported inhibitor and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections. |
| first_indexed | 2024-03-06T19:33:28Z |
| format | Journal article |
| id | oxford-uuid:1e41b39b-61d5-4f2c-8f47-53d3860bb477 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:33:28Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:1e41b39b-61d5-4f2c-8f47-53d3860bb4772022-03-26T11:15:20ZMore-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1e41b39b-61d5-4f2c-8f47-53d3860bb477EnglishSymplectic Elements at OxfordNature Publishing Group2014De Colibus, LWang, XSpyrou, JKelly, JRen, JGrimes, JPuerstinger, GStonehouse, NWalter, THu, ZWang, JLi, XPeng, WRowlands, DFry, ERao, ZStuart, DEnterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics-enhanced ligand docking and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (with IC50 of 25 pM) is an order of magnitude more potent than the best previously reported inhibitor and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections. |
| spellingShingle | De Colibus, L Wang, X Spyrou, J Kelly, J Ren, J Grimes, J Puerstinger, G Stonehouse, N Walter, T Hu, Z Wang, J Li, X Peng, W Rowlands, D Fry, E Rao, Z Stuart, D More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. |
| title | More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. |
| title_full | More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. |
| title_fullStr | More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. |
| title_full_unstemmed | More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. |
| title_short | More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. |
| title_sort | more powerful virus inhibitors from structure based analysis of hev71 capsid binding molecules |
| work_keys_str_mv | AT decolibusl morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT wangx morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT spyrouj morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT kellyj morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT renj morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT grimesj morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT puerstingerg morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT stonehousen morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT waltert morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT huz morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT wangj morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT lix morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT pengw morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT rowlandsd morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT frye morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT raoz morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules AT stuartd morepowerfulvirusinhibitorsfromstructurebasedanalysisofhev71capsidbindingmolecules |