Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site.

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ID: 77179
2019
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Abstract
Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 Å with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 Å, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 Å was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.
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wald2019cryoemproceedings Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Wald, Jiri;Pasin, Marion;Richter, Martina;Walther, Christin;Mathai, Neann;Kirchmair, Johannes;Makarov, Vadim A;Goessweiner-Mohr, Nikolaus;Marlovits, Thomas C;Zanella, Irene;Real-Hohn, Antonio;Verdaguer, Nuria;Blaas, Dieter;Schmidtke, Michaela;
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2019
DOI
10.1073/pnas.1904732116
URL
Keywords
inhibitor cryo-em 3d structure capsid binder rhinovirus

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