Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (−) and the eIF4A-inhibitor Silvestrol Journal Article
| Authors: | Müller, C.; Obermann, W.; Schulte, F. W.; Lange-Grünweller, K.; Oestereich, L.; Elgner, F.; Glitscher, M.; Hildt, E.; Singh, K.; Wendel, H. G.; Hartmann, R. K.; Ziebuhr, J.; Grünweller, A. |
| Article Title: | Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (−) and the eIF4A-inhibitor Silvestrol |
| Abstract: | Rocaglates, a class of natural compounds isolated from plants of the genus Aglaia, are potent inhibitors of translation initiation. They are proposed to form stacking interactions with polypurine sequences in the 5′-untranslated region (UTR) of selected mRNAs, thereby clamping the RNA substrate onto eIF4A and causing inhibition of the translation initiation complex. Since virus replication relies on the host translation machinery, it is not surprising that the rocaglate Silvestrol has broad-spectrum antiviral activity. Unfortunately, synthesis of Silvestrol is sophisticated and time-consuming, thus hampering the prospects for further antiviral drug development. Here, we present the less complex structured synthetic rocaglate CR-31-B (−) as a novel compound with potent broad-spectrum antiviral activity in primary cells and in an ex vivo bronchial epithelial cell system. CR-31-B (−) inhibited the replication of corona-, Zika-, Lassa-, Crimean Congo hemorrhagic fever viruses and, to a lesser extent, hepatitis E virus (HEV) at non-cytotoxic low nanomolar concentrations. Since HEV has a polypurine-free 5′-UTR that folds into a stable hairpin structure, we hypothesized that RNA clamping by Silvestrol and its derivatives may also occur in a polypurine-independent but structure-dependent manner. Interestingly, the HEV 5′-UTR conferred sensitivity towards Silvestrol but not to CR-31-B (−). However, if an exposed polypurine stretch was introduced into the HEV 5′-UTR, CR-31-B (−) became an active inhibitor comparable to Silvestrol. Moreover, thermodynamic destabilization of the HEV 5′-UTR led to reduced translational inhibition by Silvestrol, suggesting differences between rocaglates in their mode of action, most probably by engaging Silvestrol's additional dioxane moiety. © 2020 Elsevier B.V. |
| Keywords: | unclassified drug; human cell; comparative study; translation initiation; drug structure; in vitro study; drug synthesis; 5' untranslated region; epithelium cell; thermodynamics; antivirus agent; virus replication; ex vivo study; initiation factor 4a; antiviral activity; silvestrol; chromium; human; priority journal; article; eif4a; primary cell; zika virus; cr-31-b; rocaglates; rocaglate cr 31 b; coronavirinae; crimean-congo hemorrhagic fever virus; hepatitis e virus; lassa virus |
| Journal Title: | Antiviral Research |
| Volume: | 175 |
| ISSN: | 0166-3542 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2020-03-01 |
| Start Page: | 104706 |
| Language: | English |
| DOI: | 10.1016/j.antiviral.2020.104706 |
| PUBMED: | 31931103 |
| PROVIDER: | scopus |
| PMCID: | PMC7114339 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2020 -- Source: Scopus |
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