Based on synergies of several groups in the LOEWE Centre DRUID, a study on the broad-spectrum antipathogenic effect of rocaglates (compounds isolated from plants) could be published in June 2023, the results of which could be groundbreaking for the treatment of severe infectious diseases.
Rocaglates, a group of substances originally isolated from plants of the genus Aglaia (belonging to the mahogany family), play a key role in this study. Rocaglates are known for their high efficacy against RNA viruses, including highly infectious (highly pathogenic) viruses such as Ebola-, Lassa-, Crimean-Congo- and Coronaviruses. Rocaglates inhibit the RNA helicase eIF4A, which is required to unwind stable RNA structures at the beginning of protein synthesis, by fixing the bound mRNA to the surface of the enzyme. This mechanism is also known as RNA clamping. Stable RNA structural elements and/or polypurine sequences are required for clamping of the mRNA. Inhibition of eIF4A prevents these RNA structures from being unwound and, as a consequence, ribosomes cannot bind to the corresponding mRNAs. This prevents their translation into a protein and the pathogen is no longer “viable”.
Important: Viruses very often form highly structured regions in untranslated mRNA regions that are essential for their own replication. Therefore, a large number of viruses are dependent on the unwinding activity of eIF4A. Rocaglates are relatively well tolerated by humans and are already under investigation in clinical trials, which has brought this substance class into the focus of drug development during the last years and could represent a significant step forward in the treatment of viral infections and other pathogenic diseases.
Within the DRUID Centre, Prof. Arnold Grünweller has already investigated and characterized the antiviral activity of rocaglates in collaboration with various virological groups of the DRUID consortium (labs of Professors John Ziebuhr, Eberhard Hildt, Stephan Becker, Friedemann Weber). In a recent study regarding neglected tropical infectious diseases (Obermann et al., 2023), the concept of inhibition of eIF4A by rocaglates has now been extended to other pathogens, such as Schistosoma mansoni (a blood fluke that causes schistosomiasis), Trypanosoma brucei brucei (parasite that transmits African sleeping sickness), Toxoplasma gondii or Plasmodium falciparum (causative agents of toxoplasmosis or malaria), but also to the vector of yellow fever, the tiger mosquito Aedes aegypti.
Commenting on the content and results of the study, Prof. Grünweller says: “We have succeeded for the first time in providing a comprehensive picture of the antipathogenic potential of rocaglates. With the data obtained, it is in principle possible to distinguish between pathogens that are sensitive or resistant to inhibition of eIF4A by rocaglates. In addition, our results reveal potential evolutionary scenarios for the development of rocaglate resistance and provide insights into structure-activity relationships that might be useful in the synthesis of new rocaglates or other eIF4A inhibitors.”
Interestingly, the first studies with rocaglates were conducted in the context of cancer. The rocaglate zotatifin (developed by eFFECTOR Therapeutics) is currently in a Phase 2 clinical trial in pa- tients with solid tumor diseases. Inhibition of the helicase eIF4A during protein synthesis is thus not only relevant in the fight against viruses and other pathogens but is also of central importance in the field of cancer therapies.
In addition to the lab of Professor Grünweller, the labs of Professors Andreas Heine, Carlos Hermosilla, Anja Taubert, Simone Häberlein and Christoph G. Grevelding as part of the DRUID consortium were also involved in the study. The project was led by Dr. Gaspar Taroncher-Oldenburg (Philadelphia, USA) with the participation of the Sarawak Biodiversity Centre, Kuching, Malaysia.