We are interested on dissecting the roles of relevant enzymes to define their potential in therapeutics and on the intersection nutrition-disease by exploring lipid-protein interactions. The ultimate goal of our research is to discover new therapeutic targets and biomarkers, with a focus on breast cancer and metastatic progression.
Along the way we develop synergistic chemical biology methods and chemistry-based technologies, including: lipid nanodiscs, chemical phage display, chemical probes and inhibitors. We use an interdisciplinary approach that blends synthetic and medicinal chemistry, molecular biology, peptide chemistry, proteomics and cell biology, for our projects, which 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.
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. High-throughput probe development for medically relevant enzymes
Currently, there is no rapid and unbiased screening method to identify new classes of chemical probes from highly diverse pools of candidate molecules. We have recently developed a phage display methodology that allows to directly screen for specific substrate probes for a given protease target, by chemically inserting a selectivity-directing P1 site. Our approach makes use of a reactive linker which allows to form a cyclic peptide on the phage surface while simultaneously introducing a defined a P1 cleavage site and an affinity tag to immobilize the phage on beads. Using this approach, we identified cyclic peptides that are cleaved by FAP, a therapeutically relevant serine hydrolase. Our strategy enables a rapid, unbiased screening to identify new classes of highly selective substrates for diverse protease targets.
We are expanding this technology to other protein classes and different types of chemical probes.
REFS:
– F Faucher, S Lovell, M Cosco, M Bertolini, M Bogyo* & M Barniol-Xicota*. Macrocyclic Phage Display Approach for Direct Selective Protease Substrate Identification. GRC Chemistry and Biology of Peptides. Oxnard (USA). POSTER
– Marta Barniol-Xicota. Selective Substrate Identification Using Chemically Modified Phage Display. Short talk presented at the German Peptide Symposium. Jena (Germany). August 2023
– S Lovell, M Bogyo* & M Barniol-Xicota*. GRC Chemistry and Biology of Peptides. Oxnard (USA).