Organisms such as cyanobacteria, fungi and human pathogenic bacteria produce selective inhibitors of the Sec61 protein translocon complex, which translocates the vast majority of all secreted and membrane proteins across the ER membrane during their initial biogenesis (Luesch and Paavilainen, 2020). Sec61 is a dynamic protein-conducting channel with lumenal and lateral gates, and a complex gating mechanism to support correct insertion and transit of nascent polypeptides into the secretory pathway (Figure 1). A general model is emerging for how exogenous small molecules inhibit Sec61 gating to disrupt protein substrate engagement with the translocon. The first synthetic Sec61 inhibitor, KZR-261, has entered a multi-center clinical trial for metastatic solid tumors, however the mechanisms by which specific Sec61 substrates are imported into the ER from translating ribosomes is not well understood.
In collaboration with the research group of Professor Joseph Spatafora (OSU, Botany and Plant Pathology), this project is designed to elucidate evolutionary genetic patterns and processes that operate in the genomic diversification of secondary metabolism in the fungal order Hypocreales, with an emphasis on non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Shifts in nutritional mode of these fungi (e.g. leaf/wood endophytes, insect pathogens, mycoparasites) are associated with diversification of secondary metabolism. Knowledge of the phylogeny and evolution of ecologies in hypocrealean fungi may provide a predictive framework for natural product drug discovery. A current focus is the integration of evolutionary biology with secondary metabolomics and bioassay-guided isolation of selective inhibitors of cellular protein secretion (cotranslational translocation of proteins). In eukaryotic cells, the majority of secreted and membrane proteins are translocated across or integrated into the ER membrane during their biogenesis at the entrance to the cellular secretory pathway. Loss of proteostasis in the secretory pathway is implicated in major human diseases such as cancer, diabetes and inflammation, and secreted proteins are critical virulence factors for host infection by human pathogenic fungi. Thus, we aim to use natural products from fungi (and cyanobacteria) to probe the feasibility of targeting the Sec61 translocon in human diseases that remain difficult-to-treat, while avoiding toxicities associated with non-selective inhibition of secretory protein biosynthesis.