Research team
Expertise
My first degree is in the health field (Bachelor’s degree in Nursing), however due to my motivation to pursue a career in research, I continued my studies in the life sciences field. I also hold a MSc in Biology and a BSc in Biochemistry, which were awarded at Faculdade de Ciências da Universidade do Porto (Portugal). I pursued different research experiences, I studied genes of plants and invertebrates (cnidarians), and also metalloproteins from bacteria. These experiences have sparked my interest in understanding structure-function relationship of enzymes. During my PhD studies at Instituto de Tecnologia Química e Biológica António Xavier, my research was focused on the downstream steps of Base Excision Repair (BER) pathway. I have studied DNA polymerase I (DrPoll) and NAD+-dependent DNA ligase (DrLigA) from a unique bacterium, the extremophile Deinococcus radiodurans. Functional and DNA binding assays in vitro were performed to analyze DrPolI and DrLigA role and interplay in BER. Moreover, we determined the crystal structure of DrLigAΔBRCT (deletion of the C-terminal domain) and obtained a low resolution cryo-Electron Microscopy structure of the full-length DrPolI. Therefore, during my PhD studies I improved my expertise in the areas of molecular biology, biochemistry and structural biology. Currently, I am a postdoctoral fellow at University of Antwerp, and I am continuing to expand my skills and expertise in structural biology and enzymology for the study of granzymes, a family of highly homologous serine proteases.
Investigation of the interaction between GzmB and novel potent inhibitors: structural and kinetic analysis.
Abstract
Granzyme B (GzmB) is a serine protease involved in the targeted destruction of tumor cells and is stored in granules of cytotoxic T (CD8+) and natural killer (NK) cells. After perforin-mediated delivery to the tumor cell cytoplasm, GzmB is responsible for initiating caspase-mediated apoptosis. As such, GzmB is a strong candidate for monitoring tumor cell-directed killing, which renders the cytotoxic activity of CD8+ and NK cells even promising for revolutionizing cell-based anti-cancer therapies. Detecting both the presence and activity of GzmB in the tumor microenvironment (TME) can be achieved by the use of enzyme-specific activity-based probes (ABPs). However, only two such probes have been developed to date and their selectivity has not been validated. In addition, details on the structural basis of GzmB inhibition by small molecules are scarce, and this crucial to accelerate the rational design of novel inhibitors and ABPs. Thus, we aim to obtain crystals of GzmB in complex with a reference inhibitor and to determine the high resolution structure of the complex for rational drug design, and consequently to generate and characterize a library of novel GzmB inhibitors. Our findings may deliver a moiety for the future development of a novel fluorescent ABP for detection of active GzmB in the microenvironment of different solid tumors.Researcher(s)
- Promoter: Pimenta Fernandes Andreia
Research team(s)
Project type(s)
- Research Project