In this webinar, you will find the details of the project where CETSA® Explore was leveraged to study the biological mechanism of the fungal polyketide lactone Brefeldin A (BFA) in human THP-1 cells.
Fungal genomes encode a vast collection of chemical diversity that has evolved over millions of years to engage specific targets and modulate diverse biological processes. These Genetically Encoded small Molecules (GEMs) constitute a largely untapped source of potential therapeutics. Although fungal GEMs such as cyclosporine, lovastatin, and penicillin have revolutionized modern medicine, these GEMs were discovered serendipitously through bioactivity-guided fractionation of fungal extracts.
About the Presentation
LifeMine Therapeutics leveraged CETSA® Explore to study the biological mechanism of the fungal polyketide lactone Brefeldin A (BFA) in human THP-1 cells. This GEM, originally isolated from the filamentous fungus Penicillium brefeldianis, inhibits protein trafficking between the endoplasmic reticulum and the Golgi complex, eliciting antiviral, antifungal, and anticancer activity. Our CETSA® profiling study confirmed the Golgi-associated guanine nucleotide exchange factor GBF1 as the primary target of BFA, validating the established mechanism of this GEM as an inhibitor of GBF1-mediated activation of the small GTPase ARF1. These results demonstrate the utility of integrating the LifeMine GEM discovery engine with downstream proteomic profiling technologies to facilitate the mechanistic characterization of fungal GEMs en route to novel therapeutics.
Project Advisor, Pelago Bioscience
Renato Alves obtained his doctorate in biochemistry from the University of Aveiro, Portugal. In 2016, he joined a newly appointed research group, at Karolinska Institutet in Stockholm, as a postdoctoral scientist. Since 2019, he has been working for Pelago Bioscience. Initially, as a Senior Scientist, he worked closely with several drug discovery companies, planning, executing, and leading CETSA® projects in various formats adapted to the client’s needs. In 2022, he integrated the Commercial Operations team at Pelago Bioscience as a Project Advisor, where he acts as a scientific liaison for several key accounts and provides support in developing customized projects for our clients.
Senior Scientist, LifeMine Therapeutics
Ben obtained a PhD in chemistry from Emory University under the guidance of Professor Emily Weinert. His doctoral studies focused on the development of (bio)chemical tools for elucidating novel cyclic nucleotide signaling pathways in bacteria, in addition to the synthesis and biological characterization of antibacterial natural product analogues. Ben subsequently performed postdoctoral research in the group of Professor Dan Nomura at UC Berkeley, where he leveraged chemoproteomic technologies to develop novel modalities for targeted protein degradation and discover cysteine-reactive drug leads against neurodegenerative diseases. Currently, Ben is a Senior Scientist at LifeMine Therapeutics where he deploys a combination of activity- and affinity-based chemoproteomic profiling platforms in conjunction with CETSA® workflows to deconvolute the target profiles of fungal natural products and analogues en route to novel, nature-derived medicines.
About LifeMine Therapeutics
LifeMine is redefining GEM discovery through the deployment of proprietary genomic search algorithms that enable GEM target prediction a priori. Our strategy facilitates focused search-and-retrieval campaigns to rationally discover molecules selected by Nature to modulate the desired target protein. These GEM drug leads often exhibit unique structural and mechanistic features, necessitating comprehensive deconvolution of the human target profile and mechanism of action during the development process from GEM to clinical candidate.