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New insights into the Antiviral Activity and Mode of Action of Pateamines

Affiliation
Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35032 Marburg, Germany
Magari, Francesca;
Affiliation
Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35032 Marburg, Germany
Messner, Henri;
Affiliation
Institute of Medical Virology, Justus Liebig University Giessen, 35392 Giessen, Germany
Salisch, Florian;
Affiliation
Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany
Schmelzle, Stella M.;
Affiliation
Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany
Zandbergen, Ger van;
Affiliation
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany
Fürstner, Alois;
Affiliation
Institute of Medical Virology, Justus Liebig University Giessen, 35392 Giessen, Germany
Ziebuhr, John;
Affiliation
Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35032 Marburg, Germany
Heine, Andreas;
Affiliation
Institute of Medical Virology, Justus Liebig University Giessen, 35392 Giessen, Germany
Müller-Ruttloff, Christin;
Affiliation
Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35032 Marburg, Germany
Grünweller, Arnold

The SARS-CoV-2 pandemic underscored the critical need for broad-spectrum antiviral drugs. This urgency becomes more apparent as viruses mutate rapidly, rendering direct-acting antiviral approaches sometimes inefficient. Instead, host-targeting strategies can be effective by inhibiting host factors required for viral entry or replication, thereby reducing the probability for the development of drug resistance. In this context, the human RNA helicase eIF4A unwinds RNA secondary structures in the 5'-UTRs of selected mRNAs. As the protein synthesis of numerous RNA viruses relies on eIF4A, the latter is a promising target for designing broad-spectrum antivirals. It is known that potent eIF4A inhibitors such as rocaglates hinder RNA virus replication at low nanomolar concentrations through a mechanism known as RNA-clamping1. Intriguingly, pateamines, although chemically different from rocaglates, functionally mimic this clamping mechanism.
The purpose of our work is to elucidate the mode of action of eIF4A, specifically focusing on its unwinding activity at the 5'-UTR of viral mRNAs and its binding to specific inhibitors. Considering the complexity of the structures of both pateamines and rocaglates, our aim is also to develop lead candidates with more accessible synthetic routes via a structure-based approach.
In our study, we conducted a detailed analysis of 23 eIF4A variants revealing the RNA-clamping mechanism of pateamines compared to rocaglates. We integrated mutation studies, activity, and cellular assays along with molecular docking. Based on our results, an Arginine pocket appears to be crucial for the eIF4A-RNA complex formation. Our findings highlight also mechanistic differences in the binding behavior of pateamines when interacting with an eIF4A-RNA complex. Additionally, we observed that pateamines, unlike rocaglates, do not rely on the presence of polypurine tracts in RNA substrates for effective RNA clamping. Notably, pateamines exhibit remarkable anti-coronaviral activity, demonstrating potent effects in the low nanomolar range.
In summary, our study explores the roles of eIF4A and polypurine tracts in the RNA clamping mechanism of potent and selective eIF4A inhibitors. Our findings may contribute to the development of new antiviral drugs to combat potential new emerging viruses, also in the prospective of future outbreak situations.

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