Andreia Pimenta Fernandes postdoctoral scholarship hold.

Research Andreia Pimenta Fernandes

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. 01/04/2024 - 31/03/2025

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)

Research team(s)

Project type(s)

  • Research Project

Tackling the challenges in selective and potent targeting of Tumor Micro-Environment Proteases. 01/11/2022 - 31/10/2024

Abstract

Various proteases play an important role in the tumor microenvironment (TME). Hence, tackling tumors by targeting these TME proteases is a very promising approach in the fight against cancer. FAPIs, highly potent and selective probes based on UAMC1110, an inhibitor developed at the UAntwerp, are currently evaluated in clinical studies. In contrast, the targeting of other highly relevant TME proteases is lagging behind. Granzyme B (GRZB) is the most abundant protease present in the granules of cytotoxic immune cells present in the TME and plays a role in the targeted tumor cell destruction. Despite decades of research, many aspects of GRZB immunobiology remain enigmatic. It is currently unknown which percentage of GRZB is active in the TME. To study whether imaging or measuring active GRZB levels has advantages over visualizing total GRZB, there is a need for selective and high affinity GRZB probes. Given the potential of GRZB in cancer diagnosis and treatment, this postdoc challenge aims to reinvigorate the quest for the generation of highly selective GRZB inhibitors starting from a literature-based lead compound. The postdoc will be challenged to determine the high-resolution structure of this inhibitor – GRZB complex to fuel rational ligand design. The labs participating in this call are involved in the recently funded OncoProTools (Protease-guided tumor targeting tools to revolutionize cancer diagnostics and treatment) HE-MSCA-Doctoral Network (granted upon first submission, UAntwerp as the lead applicant). UAntwerp will host two PhD students (PhD1 and PhD2) from January 2023 onwards. Since this international project will be the start of a new GRZB-research line within the 'Tumor Micro-environment Proteases' theme, support by a postdoc is highly desirable. The project will be supported by docking studies for in silico design of new inhibitors (UAMC, Hans De Winter). We will offer in-house access to granzyme activity assays, recombinant protein production and purification infrastructure, protein-ligand interaction assays and a lab fully equipped for structural biology (LMB, Y. Sterckx). The Postdoc candidate is expected to bring own experimental expertise with protein expression and structural biology into the GRZB theme and he/she will benefit from a dynamic international network of academic and industrial partners in the field of oncology.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project