ITQB: IMAC - MA Dissertations
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- Cyclophilin D as a multiple sclerosis and cardiovascular disease drug targetPublication . Freitas, Micael Correia; Bandeiras, Tiago; Matias, Pedro"Cyclophilins belong to the immunophilin family and are peptidyl-prolyl isomerases (PPIases) which catalyze the cis-trans interconversion of proline isomers in other proteins, an important step of protein folding. They are widely distributed in all organisms highly conserved throughout evolution. They were originally identified as the biological receptors for immunosuppressants such as Cyclosporine A, highly used to prevent immune response and organ rejection after a transplant. This immunosuppressant effect was determined to be unrelated to the intrinsic isomerase activity. They are known to be involved in pathophysiological process such as inflammation and vascular dysfunction, innate immunity to HIV, hepatitis C infection, neurodegenerative and pathological conditions and tumor biology. In particular, cyclophilin D (CypD), the mitochondrial isoform of the enzyme, is a key regulator of the mitochondrial permeability transition pore. Mitochondrial disfunction has been implicated in multiple sclerosis as well as in cardiovascular disease, suggesting CypD as a potential drug target. Following up on the increased awareness of CypD impact in human health, both pockets (proline and aniline) were screened following a Fragment-Based Drug Discovery approach at Merck KGaA (Darmstadt, Germany) where 58 confirmed fragments hits were obtained, from which only 6 CypD-fragment 3D crystal structures could be obtained.(...)"
- CRYSTAL STRUCTURE OF BONE MARROW TYROSINE KINASE FROM CHROMOSOME X WITH COVALENT LIGANDSPublication . Sousa, Bárbara Beatriz da Costa Botelho; Matias, Pedro"Bone marrow tyrosine kinase in chromosome X (BMX) is a major member of the TEC family kinases and has been implicated in tumorigenecity, motility, proliferation and differentiation. BMX is highly overexpressed in prostate cancer and it is involved in the adaptive compensatory mechanism of castrate-resistance prostate cancer to androgen deprivation therapy. Besides, it suppresses a core component of the intrinsic apoptotic pathway, granting tumor cells the ability to escape apoptosis induced by chemotherapeutic drugs. BMX knockout mouse have a normal lifespan, without an obvious altered phenotype, suggesting that therapies based on BMX inhibition, may have limited side effects. We developed a series of BMX-IN-1 analogues that showed an increased inhibitory capacity when compared to BMX-IN-1. Since crystallographic information is essential to understand the molecular basis of BMX inhibition by covalent inhibitors we establish a baculovirus-insect expression system protocol for the production of the recombinant human BMX. Here we report the full biochemical and biophysical characterization of human BMX alone and in complex with different covalent ligands.(...)"