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Abstract

Pateamines, derived from the sponge Mycale hentscheli, function as inhibitors of the RNA helicase eIF4A and exhibit promising antiviral and anticancer properties. eIF4A plays a pivotal role in unwinding stable RNA structures within the 5′-UTR of selected mRNAs, facilitating the binding of the 43S preinitiation complex during translation initiation. Pateamines function by clamping RNA substrates onto the eIF4A surface, effectively preventing eIF4A from carrying out the unwinding step. Rocaglates, a compound class isolated from plants of the genus Aglaia, target the same binding pocket on eIF4A, and based on structural data, a similar mode of action has been proposed for pateamines and rocaglates. In this study, we conducted a detailed characterization of pateamines' binding mode and assessed their antiviral activity against human pathogenic coronaviruses (human coronavirus 229E (HCoV-229E), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)). Our findings reveal significant differences in the binding behavior of pateamines compared to rocaglates when interacting with an eIF4A-RNA complex. We also observed that pateamines do not depend on the presence of a polypurine tract in the RNA substrate for efficient RNA clamping, as it is the case for rocaglates. Most notably, pateamines demonstrate potent antiviral activity against coronaviruses in the low nanomolar range. Consequently, pateamines broaden our toolbox for combating viruses that rely on the host enzyme eIF4A to conduct their viral protein synthesis, indicating a possible future treatment strategy against new or re-emerging pathogenic viruses.