FLORIO, DANIELE (2024) Amyloid modulation in disordered proteins: role in Acute Myeloid Leukemia and neurodegenerative diseases. [Tesi di dottorato]

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Abstract

Amyloidosis concerns a group of severe diseases, characterized by anomalous accumulations of protein aggregates determining deep alterations of the physiological functions. causing neurodegenerative diseases (NDDs). Amyloid fibers are insoluble aggregates of proteins or peptides structurally characterized by an extended β conformation able to self-recognize in the so-called amyloid aggregation process. Previous studies highlighted a strong propensity to amyloid aggregation of some regions of the C-terminal domain (CTD) of Nucleophosmin 1 (NPM1), an abundant multifunctional nucleolar chaperone which results mutated in its CTD, in Acute Myeloid Leukemia (AML) with an aberrant cytoplasmatic localization (NPMc+). To further investigate the molecular mechanisms associated with misfolding and mislocation of NPMc+, several studies were carried out: the amyloidogenic features of type C mutation as well as the existence of other hot spots of aggregation in the remaining regions of the protein (N-Terminal domain (NTD) and the central intrinsically disordered region (IDR)) were deepened. To exploit this amyloidogenicity for therapeutic purposes, two studies concerning the identification of external agents as enhancer of amyloid aggregation to selectively induce cytotoxicity of leukemic cells following a "cell starvation strategy”, were conducted. The first concerned two analogues of orcein containing the dihydroquinazolin and hexahydroquinoline as pharmacophores and the second designed peptides analogues of NPM1264-277 In addition, within the 264-277 fragment of NPM1, several ultrashort bioinspired self-aggregating peptides were investigated in their gelling features and biocompatibility as well as the effects of His point substitutions in the same protein region. This region was also employed as an amyloid template to test several ruthenium-based complexes as inhibitors of aggregation.

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