Natural products as drugs and tools for influencing core processes of eukaryotic mRNA translation

Abstract

Eukaryotic protein synthesis is the highly conserved, complex mechanism of translating genetic information into proteins. Although this process is essential for cellular homoeostasis, dysregulations are associated with cellular malfunctions and diseases including cancer and diabetes. In the challenging and ongoing search for adequate treatment possibilities, natural products represent excellent research tools and drug leads for new interactions with the translational machinery and for influencing mRNA translation. In this review, bacterial-, marine- and plant-derived natural compounds that interact with different steps of mRNA translation, comprising ribosomal assembly, translation initiation and elongation, are highlighted. Thereby, the exact binding and interacting partners are unveiled in order to accurately understand the mode of action of each natural product. The pharmacological relevance of these compounds is furthermore assessed by evaluating the observed biological activities in the light of translational inhibition and by enlightening potential obstacles and undesired side-effects, e.g. in clinical trials. As many of the natural products presented here possess the potential to serve as drug leads for synthetic derivatives, structural motifs, which are indispensable for both mode of action and biological activities, are discussed. Evaluating the natural products emphasises the strong diversity of their points of attack. Especially the fact that selected binding partners can be set in direct relation to different diseases emphasises the indispensability of natural products in the field of drug development. Discovery of new, unique and unusual interacting partners again renders them promising tools for future research in the field of eukaryotic mRNA translation.

Keywords: 13-deoxytedanolide (PubChem CID: 16040283); Agelastatin A (PubChem CID: 177936); Bruceantin (PubChem CID: 5281304); Bruceine D (PubChem CID: 441788); Brusatol (PubChem CID: 73432); Candidaspongiolides (PubChem CID: 102471178); Chemical biology; Chlorolissoclimide (PubChem CID: 127675); Cycloheximide (PubChem CID: 6197); Cytotrienin A (PubChem CID: 11966097); Dehydrodidemnin B (PubChem CID: 9812534); Dichlorolissoclimide (PubChem CID: 10549927); Didemnin B (PubChem CID: 13895197); Didesmethylrocaglamide (PubChem CID: 397614); Drug development; Episilvestrol (PubChem CID: 11467934); Eudistomin C (PubChem CID: 184887); Eukaryotic protein synthesis; Gephyronic acid (PubChem CID: 52952026); Girodazole (PubChem CID: 131917); Harringtonine (PubChem CID: 276389); Heamanthamine (PubChem CID: 441593); Hippuristanol (PubChem CID: 9981822); Homoharringtonine (PubChem CID: 285033); Irciniastatin A (PubChem CID: 44424682); Iso-migrastatin (PubChem CID: 15940571); Lactimidomycin (PubChem CID: 11669726); Lycorine (PubChem CID: 72378); Mycalamide A (PubChem CID: 10345974); Mycalamide B (PubChem CID: 6711419); Myriaporone 3 (PubChem CID: 71306325); Myriaporone 4 (PubChem CID: 100917959); Nagilactone C (PubChem CID: 319648); Nagilactone E (PubChem CID: 457159); Nannocystin A (PubChem CID: 132087316); Narciclasine (PubChem CID: 72376); Natural product; Onnamide A (PubChem CID: 23426006); Pateamine A (PubChem CID: 10053416); Pederin (PubChem CID: 5381287); Resveratrol (PubChem CID: 445154); Rocaglamide (PubChem CID: 331783); Rocaglaol (PubChem CID: 393602); Silvestrol (PubChem CID: 11787114); Sparsomycin (PubChem CID: 5364216); Streptimidone (PubChem CID: 5351572); Streptovitacin A (PubChem CID: 91467); Tedanolide (PubChem CID: 5478005); Tedanolide C (PubChem CID: 11851217); Theopederin B (PubChem CID: 134820451); Translation inhibition; Translational machinery; Vioprolide A (PubChem CID: 153274465).