Mammalian cells also express a second eIF4A paralog (known as eIF4A2) that shares 90% amino acid identity with eIF4A1 and has been shown to participate in translation initiation ( Rogers et al., 2002 Yoder-Hill et al., 1993). A rocaglate-resistant eIF4A1 mutant (F163L) has been characterized and introduction of this allele into cells using CRISPR/Cas9-mediated gene editing confers resistance to rocaglate cytotoxicity ( Chu et al., 2016 Iwasaki et al., 2019), further demonstrating that the mechanism of action of these compounds is dependent on their ability to interfere with eIF4A1 activity. When present within 5’ mRNA leader regions, polypurine sequences serve as nucleation sites for rocaglate:eIF4A1 complexes, leading to the formation of steric barriers that impede 43S PIC scanning ( Iwasaki et al., 2016). Structural elucidation of a rocaglate:eIF4A1:polypurine RNA complex revealed that rocaglates function as interfacial inhibitors and make critical contacts with eIF4A1 (F163L, Q195) and two adjacent RNA purine bases ( Iwasaki et al., 2019). Assembly of the eIF4F complex is under mTOR regulation, ensuring that rheostatic and selective regulation of mRNA translation is linked to extra- and intra-cellular cues ( Pelletier and Sonenberg, 2019). Only ~5% of eIF4A is present in the eIF4F complex, suggesting that multiple eIF4A molecules may be used per initiation round and/or eIF4A may have non-eIF4F related activities in translation ( Sokabe and Fraser, 2017). The dependency on eIF4F for ribosome recruitment by different mRNAs varies and scales with the degree of 5’ leader secondary structure ( Svitkin et al., 2001). Studies using silvestrol, a natural product isolated from Aglaia foveolata, indicate that rocaglates enhance the RNA binding affinity of the DEAD-box RNA helicase, eukaryotic initiation factor (eIF) 4A ( Bordeleau et al., 2008 Iwasaki et al., 2016).Ĭap-dependent translation is regulated by the rate-limiting eIF4F complex which recognizes mRNA cap structures via its eIF4E subunit, remodels adjacent mRNA structure via eIF4A, and recruits 43S pre-initiation complexes (40S subunit and associated factors) through its eIF4G subunit ( Pelletier and Sonenberg, 2019). To date, numerous rocaglate analogs have been synthesized with the goals of improving potency and bioavailability ( Ebada et al., 2011 Pan et al., 2014 Ribeiro et al., 2012).
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This family of small molecules shares a common cyclopentabenzofuran core and were originally isolated from extracts of the Aglaia species of angiosperms ( King et al., 1982). Rocaglates are a class of translation inhibitors that possess potent cytotoxic activity against tumor cells ( Bhat et al., 2015). In particular, there is significant interest towards the development of a family of compounds collectively known as rocaglates ( Bhat et al., 2015). Small molecules targeting the translation machinery show considerable promise in the treatment of a variety of human maladies including cancer, viral infection, and neurodegeneration. These compounds are among the most potent rocaglates documented to date, and taken together, this work offers important information that will guide the future design of rocaglates with improved biological properties. Through this, we report on the identification and characterization of a potent class of synthetic rocaglates called amidino-rocaglates. To further our understanding of rocaglate diversity and drug design, herein we explore the RNA clamping activity of >200 unique rocaglate derivatives. There is significant interest in the development and expansion of rocaglate derivatives as several members of this family have been shown to possess potent anti-neoplastic activity in vitro and in vivo. Working as interfacial inhibitors, rocaglates stabilize the association between eIF4A and RNA which can lead to the formation of steric barriers that block initiating ribosomes.
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Rocaglates share a common cyclopentabenzofuran core that inhibit eukaryotic translation initiation by modifying the behaviour of the RNA helicase, eIF4A.