Dziekan, J. | bioRxiv Science

bioRxiv2022

Genomic, transcriptomic, and metabolomic analysis of Traditional Chinese Medicine plant Oldenlandia corymbosa reveals the biosynthesis and mode of action of anti-cancer metabolites

Natural products from traditional medicinal plants are valuable candidates for clinical cancer therapy. Plants from the Oldenlandia-Hedyotis complex are popular ingredients of Traditional Chinese Medicine (TCM), however a major hurdle in the plant bioprospecting process of TCM plants is that the active metabolites, their biosynthetic pathways, and mode of action are often unknown. We show that Oldenlandia corymbosa extracts are active against breast cancer cell lines. To study the genes involved in the biosynthesis of active compounds in this medicinal plant, we assembled a high-quality genome. We show that the main active compound is ursolic acid and that abiotic stresses cause changes in anti-cancer activity, metabolite composition, and gene expression of plants. To reveal the mode of action of ursolic acid, we show that cancer cells undergo mitotic catastrophe, and we identify three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking.

plant biology↗

bioRxiv2021

Identification of an inhibitory pocket in falcilysin bound by chloroquine provides a new avenue for malaria drug development

Despite their widespread use, our understanding of how many antiparasitic drugs work remains limited. We used mass-spectrometry based cellular thermal shift assay (MS-CETSA) to identify possible protein targets of several malaria drugs and drug candidates. We found that falcilysin (FLN) is a common target for several quinoline drugs including chloroquine and mefloquine, as well as drug candidates MK-4815, MMV000848 and MMV665806. At pH 7.5, these compounds all inhibit FLN proteolytic activity with IC50 values ranging from 1.6 to 67.9 {micro}M. Their interaction with FLN was systematically probed by isothermal titration calorimetry and X-ray crystallography, revealing a shared hydrophobic pocket in the catalytic chamber of the enzyme. Characterization of transgenic cell lines with depleted FLN expression demonstrated statistically significant increases in susceptibility towards chloroquine, mefloquine, MK-4815 and MMV000848. Taken together, our findings point to a multimodal mechanism of action for several commonly used anti-malaria drugs. Importantly, a common allosteric pocket of FLN appears amenable to inhibition, providing a structural basis to guide the development of novel drugs against malaria.

microbiology↗