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CCBIO seminar: Aurora Martinez

Pharmacological chaperoning: a potential treatment for genetic diseases, including some cancer syndromes

Aurora Martinez
Department of Biomedicine, University of Bergen

Many inherited disorders are associated with disturbances of anabolic or catabolic pathways in cell metabolism, affecting the synthesis, degradation and storage of biomolecules. These disorders, collectively known as inborn errors of metabolism (IEM), are typically caused by mutations in enzyme-coding genes and, although each of these disorders is rare, the overall incidence of IEM is approx. 1 in 2000 births worldwide. Nevertheless, developing effective therapies for IEM has proven to be challenging. Increasing knowledge on the pathogenic mechanisms has revealed that most IEM-associated mutations lead to loss-of-function by destabilization and misfolding of the coded enzymes. Despite complex quality control systems, mutant proteins are not completely rescued and the misfolding may cause either their increased degradation or aggregation. This understanding points to pharmacological chaperones (PC) as promising strategies for IEM correction. PCs are small molecular weight compounds that prevent and/or correct the instability and misfolding by selectively binding to key sites of the mutant proteins. Our research group has together with collaborators developed protocols for the screening, discovery and validation of compounds for conformational stabilization of specific enzymes associated with IEM, for which phenylketonuria is the model disease. In general, the discovered compounds show large promise for the development of PCs. Recently, we have used a similar strategy to discover compounds that correct the conformational defect caused by mutations in nucleophosmin (NPM), a nucleolar protein involved in ribosome assembly and cell homeostasis. The mutations lead to cytoplasmic localization and aggregation of NPM, and are associated with acute myeloid leukemia (AML). Through high-throughput screening we have identified stabilizing hit-compounds that bind to a particular hydrophobic pocket in NPM and show chaperoning potential. In cells expressing NPM, the best hits partially alleviated the aggregation and restored nucleolar localization of misfolded mutants. The identified hits appear promising for PC-based therapies for AML, based on conformational stabilization of NPM.

Chairperson: Camilla Krakstad, CCBIO