Magari Francesca, Messner Henri, Salisch Florian, Schmelzle Stella M, van Zandbergen Ger, Fürstner Alois, Ziebuhr John, Heine Andreas, Müller-Ruttloff Christin, Grünweller Arnold
Institute of Pharmaceutical Chemistry, Philipps University Marburg, 35032, Marburg, Germany.
Institute of Medical Virology, Justus Liebig University Giessen, 35392, Giessen, Germany.
Heliyon. 2024 Jun 22;10(13):e33409. doi: 10.1016/j.heliyon.2024.e33409. eCollection 2024 Jul 15.
Pateamines, derived from the sponge , 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 , 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.
从海绵中提取的帕特胺类化合物可作为RNA解旋酶eIF4A的抑制剂，并展现出有前景的抗病毒和抗癌特性。eIF4A在解开特定mRNA 5'-UTR内的稳定RNA结构中起关键作用，在翻译起始过程中促进43S预起始复合物的结合。帕特胺类化合物通过将RNA底物夹在eIF4A表面发挥作用，有效阻止eIF4A进行解旋步骤。从某种植物属中分离出的洛卡类化合物靶向eIF4A上的相同结合口袋，基于结构数据，已提出帕特胺类化合物和洛卡类化合物有相似的作用模式。在本研究中，我们对帕特胺类化合物的结合模式进行了详细表征，并评估了它们对人类致病性冠状病毒（人类冠状病毒229E（HCoV-229E）、严重急性呼吸综合征冠状病毒2（SARS-CoV-2））的抗病毒活性。我们的研究结果显示，与洛卡类化合物相比，帕特胺类化合物在与eIF4A-RNA复合物相互作用时，其结合行为存在显著差异。我们还观察到，与洛卡类化合物不同，帕特胺类化合物在有效夹住RNA时不依赖于RNA底物中多聚嘌呤序列的存在。最值得注意的是，帕特胺类化合物在低纳摩尔范围内对冠状病毒表现出强大的抗病毒活性。因此，帕特胺类化合物拓宽了我们对抗依赖宿主酶eIF4A进行病毒蛋白合成的病毒的工具库，表明了未来针对新出现或再次出现的致病病毒的一种可能治疗策略。
