Identifying the target of the natural product cordycepin

About the Project

Natural products are historically proven to be excellent drug leads, but they have been largely ignored in western medicine in recent years. This is unwise because traditional knowledge is being ignored, but also because natural products have been selected by evolution and can give us new insights in health and disease. For instance, caterpillar fungi (known as Cordyceps) are famous in Chinese traditional medicine. Cordycepin, produced by Cordyceps militaris, has been shown to be effective in a large number of disease models, including in our laboratories (Ashraf 2019, Lawrence 2025), and the cordycepin derivative NUC-7738 of this molecule is in clinical trials. Through a systematic review of the literature and an extensive systems pharmacology study (Radhi 2021, Lawrence 2025), we have shown that cordycepin primarily acts by suppressing the MEK/ERK and PI3K/AKT/mTOR signal transduction pathways in all cells examined. It is however also clear that cordycepin is an inhibitor of the last step of mRNA synthesis, polyadenylation. Moreover, knockdown of polyadenylation machinery can have similar effects to cordycepin (Wong 2010, Kondrashov 2012, Ashraf 2019). The data therefore indicate that cordycepin acts through a so far unrecognised dependence of signal transduction on polyadenylation. To study the effects of cordycepin on polyadenylation, we have now developed a suite of biochemical and bioinformatics methods to look at poly(A) tail sizes genomewide ( using a variant of Nanopore sequencing) as well as at individual mRNAs. In addition, we have gained expertise in doing haploid genetic screens to elucidate the mechanism of action of cordycepin. Now that all the methods are in place, we are looking for a PhD student with a proven interest in molecular biology and/or bioinformatics data analysis to complete this project. They will prepare samples for Nanopore sequencing as well as perform a large scale haploid genetic screen and analyse these data to identify candidate targets of cordycepin. These findings will be confirmed experimentally by for instance measuring changes in signal transduction (eg western blot, ELISA, microscopy) after knockdown or mutation of mRNAs and/or non-coding RNAs that are candidates to be the molecular target of cordycepin. Skills gained in this project will include advanced experimental molecular biology and deep bioinformatic analysis, including coding. This project is likely to lead to both fundamental new insights in cell biology as well as contribute to the development of a novel class of anti-inflammatory and cancer medicines, the polyadenylation inhibitors.

Funding Notes

We will offer help with scholarship applications to successful applicants, if required.