Immunology, Transplantation and Infectious diseases
Biocrystallography
The interest of our group is the understanding the molecular mechanisms at the roots of the function of biological macromolecules and their implication in human disease. We employ an integrated structural biology approach to characterize proteins and their functional complexes to dissect their physiological role, and harness their activity to develop novel disease-modifying strategies.
Research activity
One of our current areas of interest spans from a collaboration with groups working on clinical aspects of lymphomas such as chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL) and multiple myeloma (MM). CLL is a leukemia with a highly heterogeneous manifestation in patients, and current treatments are only partially effective. Most importantly, the available therapeutic options do not fully consider the inter-patient variability of the disease that ranges between indolent and rapidly progressing with an urgent need of treatment. Our previous biochemical and structural analysis of B-cell receptors (BCR) from leukemic cells that showed an unprecedented, subtype-specific autologous recognition that leads to intracellular signaling that sustains the pathogenic proliferation. Moreover, we showed how indolent CLL is associated with strong, persistent BCR homotypic interactions. We are applying structural, biochemical and in silico approaches to identify subset-specific BCR antagonists that could be employed in a clinical setting to individually benefit patients, towards a highly-personalized treatment of both CLL and SMZL.
We use a different approach towards new therapies for persons with MM, a neoplastic disease of clonal antibody-producing plasma cells. Specifically, we are identifying novel vulnerabilities in mitochondrial processes that, when disrupted, can achieve the dual goal of hampering myeloma cells survival and “reawakening” the immune response towards the tumor. Currently, we are using cryo-electron microscopy, X-ray crystallography and docking calculations to characterize the human mitochondrial protease ClpPX system. Transcriptomic and knockdown data highlighted the dependency of MM cells survival on the ClpP proteolytic subunit, thus prompting the identification of specific compounds to inhibit its activity in vivo. We are developing novel compounds to achieve this goal and testing them in vitro, establishing a pipeline that will be also applied to newly identified mitochondrial targets.
