Our lab explores how poorly understood enzymes and membrane proteins shape immunity, metabolism, and disease progression. We focus on molecular players that sit at the interface of immunology and pathology, alongside key regulators of lipid metabolism and intramembrane proteolysis. A central goal of our research is to uncover new therapeutic targets, actionable biomarkers, and mechanistic insights relevant to cancer biology, especially breast cancer and metastatic progression.
To tackle these uncharted targets, we build powerful chemical biology tools and chemistry-based technologies, including: high-throughput assays, chemical and phage-based screens, lipid nanodiscs, macrocyclic peptides, activity based probes and precision inhibitors. Blending synthetic medicinal chemistry, molecular biology, peptide chemistry, proteomics and cell biology, we aim to translate mechanistic insight into new diagnostic biomarkers and therapeutic strategies. Our projects include:
Research line 1. Lipid metabolism as target for breast and drug resistant cancers.
Aberrant lipid metabolism and altered plasma membrane composition are characteristics of cancerous cells affecting cell survival, proliferation and response to therapeutics. This process is driven by the dysregulation of lipid metabolism, including the key enzyme family lysophosphatidylcholine-acyltransferases (LPCATs), which synthesize phosphatidylcholine (PC) by adding specific fatty acids (FA) to lysophosphatidylcholine (LPC). Members of this family, namely LPCAT1 and 2 have preference for saturated FA, and therefore increase the overall saturation and stiffness of the membrane through their activity. Importantly, these enzymes are overexpressed in several kinds of cancer, including breast cancer where they have been linked to poor prognosis (LPCAT1) and drug resistance (LPCAT2). Here we aim to provide a chemical biology solution, in the form of new chemical tools and inhibitors, to characterize these enzymes, elucidate their role as cancer invasion drivers and exploit their potential as antineoplastic targets and biomarkers.
Research line 2. Targeting intramembrane proteolysis in human pathology.
Intramembrane proteases (IMP) are a paradigmatic class of proteolytic enzymes that are embedded in the lipid bilayer, where they cleave their transmembrane substrates. The potential of IMPs to become drug targets is underlined by the recent approval of the first IMP inhibitor, Nirogacestat, for rare tumors. The serine subclass of IMPs, also called rhomboid proteases, are the most ubiquitous IMPs in nature and are involved in several debilitating human diseases, including cancer or neurodegeneration. We mainly focus on the human rhomboids located in the secretory pathway and termed RHBDL1-4. Across these systems, we are particularly interested in deciphering lipid–protein interactions and how membrane environments influence enzyme activity, substrate selectivity and signaling.
REFS:
– Barniol-Xicota M. & Verhelst S. H. L. Functional Rhomboid Proteases in Lipid Nanodiscs by Using Diisobutylene/Maleic Acid Copolymers. J Am Chem Soc 2018 140 44 14557-14561.
– Beard H A, Barniol-Xicota M, Yang J, Verhelst SHL. Discovery of Cellular Roles of Intramembrane Proteases. ACS Chem Biol. 2019;14(11):2372-2388. doi:10.1021/acschembio.9b00404
Research line 3. Immune-focused tool development
We build novel chemical and peptide-based tools to probe immune-cell–restricted proteases, including novel pathways that control cytotoxic function. In parallel, we design strategies to target immune receptors for selective delivery of cargo, enabling precise interrogation and modulation of immune responses in relevant environments. These approaches open new avenues to understand immune regulation and identify actionable targets for immunotherapy. Our approach allows us to interrogate enzyme activity in complex immune environments, providing insight into mechanisms that control antigen presentation and immune regulation.
Research line 4. Precision diagnostics through high-throughput probe discovery
We develop high-throughput screening strategies to discover chemical probes for medically relevant enzymes, enabling the rapid identification of selective biomarkers. By combining cyclic peptide design, reactive linkers, and phage-display technology, we can map enzyme activity across diverse protein families. These probes serve not only as research tools but also as foundations for precision diagnostics and translational applications in disease
We are expanding this technology to other protein classes and different types of chemical probes.
REFS:
– Faucher FF, Blažková K, Lovell S, Bertolini M, Herrero-Bourdieu J, Cosco ED, Bogyo M, Barniol-Xicota M. Macrocyclic phage display for identification of selective protease substrates. J Am Chem Soc. 2025 10.1021/jacs.5c04424