Parasitic helminths remain a significant public health problem in many parts of the world. Helminths infect over 2 billion people, can decrease physical and cognitive development in children, lead to considerable morbidity, and hinder socioeconomic development in endemic areas. The identification and characterization of new potential drug targets is warranted as examples of drug resistance have been identified. In addition, the development of broader spectrum targets and drugs would be extremely valuable. One intriguing potential target is the parasite translation initiation factor eIF4E. eIF4E recognizes the mRNA cap and is a key and rate-limiting step in translation. Vertebrate host eIF4E is highly specific for a monomethylguanosine eukaryotic cap, and this is the only cap present on vertebrate mRNAs. In contrast, we have shown that Ascaris and schistosome eIF4Es have similar affinities for both the trimethyl- and monomethylguanosine caps. Thus, parasitic helminth eIF4Es have the unique ability to recognize trimethylguanosine (TMG) caps compared with their vertebrate eIF4E counterparts. Many mRNAs in parasitic helminths have a TMG cap. Approximately 10% (schistosomes) to 90% (Ascaris) of helminth mRNAs acquire a TMG cap through a special type of splicing known as spliced leader RNA trans-splicing. Trans-splicing generates the mature 5'ends of mRNAs and adds the specialized TMG cap to helminth mRNAs. All major groups of parasitic helminths exhibit spliced leader trans-splicing. Recognition of the TMG cap is essential for translation of helminth mRNAs and eIF4E is essential in C. elegans. To understand the biochemical and biophysical basis for helminth eIF4E recognition of the TMG cap, we propose to carry out X-ray crystallography and NMR studies on helminth eIF4E bound to the TMG cap, m2,2,7GpppG. Information from these studies will provide insight into the key interactions and mechanism of TMG-cap binding by parasite eIF4E. This information will help direct rational mutagenesis studies to further define important eIF4E-TMG cap interactions. Overall, these studies will identify key features of TMG cap recognition that may enable future studies directed at designing specific cap analogs to target the unique substrate binding attributes of eIF4E present in a broad spectrum of important helminth infections.
Parasitic helminths remain a significant public health problem in many parts of the world and hinder socioeconomic development in endemic areas. We will carry out structural analyses of an essential parasite protein, eIF4E, with unique substrate specificity for the mRNA cap to evaluate this protein as a potential target for new and novel therapeutics against parasitic helminths.
| Piecyk, Karolina; Davis, Richard E; Jankowska-Anyszka, Marzena (2012) Synthesis of N²-modified 7-methylguanosine 5'-monophosphates as nematode translation inhibitors. Bioorg Med Chem 20:4781-9 |
| Piecyk, Karolina; Davis, Richard E; Jankowska-Anyszka, Marzena (2012) Synthesis of ýýýýC- and ýýýýýC-labeled dinucleotide mRNA cap analogues for structural and biochemical studies. Bioorg Med Chem Lett 22:4391-5 |
| Liu, Weizhi; Jankowska-Anyszka, Marzena; Piecyk, Karolina et al. (2011) Structural basis for nematode eIF4E binding an m(2,2,7)G-Cap and its implications for translation initiation. Nucleic Acids Res 39:8820-32 |
| Liu, Weizhi; Zhao, Rui; McFarland, Craig et al. (2009) Structural insights into parasite eIF4E binding specificity for m7G and m2,2,7G mRNA caps. J Biol Chem 284:31336-49 |
