Your browser doesn't support javascript.
Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (-) and the eIF4A-inhibitor Silvestrol.
Müller, Christin; Obermann, Wiebke; Schulte, Falk W; Lange-Grünweller, Kerstin; Oestereich, Lisa; Elgner, Fabian; Glitscher, Mirco; Hildt, Eberhard; Singh, Kamini; Wendel, Hans-Guido; Hartmann, Roland K; Ziebuhr, John; Grünweller, Arnold.
  • Müller C; Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392, Gießen, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the Partner Site Gießen-Marburg-Langen, Germany.
  • Obermann W; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
  • Schulte FW; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
  • Lange-Grünweller K; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
  • Oestereich L; Bernhard-Nocht-Institut für Tropenmedizin, Abteilung Virologie, Hamburg, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the Partner Site Hamburg, Germany.
  • Elgner F; Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und Biomedizinische Arzneimittel, Abteilung Virologie, Paul-Ehrlich-Straße 51-59, 63225, Langen, Germany.
  • Glitscher M; Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und Biomedizinische Arzneimittel, Abteilung Virologie, Paul-Ehrlich-Straße 51-59, 63225, Langen, Germany.
  • Hildt E; Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und Biomedizinische Arzneimittel, Abteilung Virologie, Paul-Ehrlich-Straße 51-59, 63225, Langen, Germany.
  • Singh K; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10023, USA.
  • Wendel HG; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10023, USA.
  • Hartmann RK; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
  • Ziebuhr J; Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen, Schubertstraße 81, 35392, Gießen, Germany; Deutsches Zentrum für Infektionsforschung (DZIF) at the Partner Site Gießen-Marburg-Langen, Germany.
  • Grünweller A; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032, Marburg, Germany. Electronic address: arnold.gruenweller@staff.uni-marburg.de.
Antiviral Res ; 175: 104706, 2020 03.
Article in English | MEDLINE | ID: covidwho-2162
Semantic information from SemMedBD (by NLM)
1. DNA Sequence COEXISTS_WITH 5\' Untranslated Regions
Subject
DNA Sequence
Predicate
COEXISTS_WITH
Object
5\' Untranslated Regions
2. 5\' Untranslated Regions INTERACTS_WITH RNA
Subject
5\' Untranslated Regions
Predicate
INTERACTS_WITH
Object
RNA
3. DNA Sequence DISRUPTS translation initiation complex
Subject
DNA Sequence
Predicate
DISRUPTS
Object
translation initiation complex
4. Bronchial Epithelial Cell LOCATION_OF B-Complex
Subject
Bronchial Epithelial Cell
Predicate
LOCATION_OF
Object
B-Complex
5. DNA Sequence COEXISTS_WITH 5' Untranslated Regions
Subject
DNA Sequence
Predicate
COEXISTS_WITH
Object
5' Untranslated Regions
6. 5' Untranslated Regions INTERACTS_WITH RNA
Subject
5' Untranslated Regions
Predicate
INTERACTS_WITH
Object
RNA
7. DNA Sequence DISRUPTS translation initiation complex
Subject
DNA Sequence
Predicate
DISRUPTS
Object
translation initiation complex
8. Bronchial Epithelial Cell LOCATION_OF B-Complex
Subject
Bronchial Epithelial Cell
Predicate
LOCATION_OF
Object
B-Complex
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Triterpenes / Virus Replication / Viruses / Benzofurans Limits: Animals / Humans Language: English Journal: Antiviral Res Year: 2020 Document Type: Article Affiliation country: J.antiviral.2020.104706

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Triterpenes / Virus Replication / Viruses / Benzofurans Limits: Animals / Humans Language: English Journal: Antiviral Res Year: 2020 Document Type: Article Affiliation country: J.antiviral.2020.104706