Etudes structurales, fonctionnelles et d'inhibition de l'histone déacétylase 7 humaine
Year: 2010
Type: dissertation
Abstract: Atherosclerosis occurs due to accumulation of cholesterol in the arteries leading to rigid plaque formation leading eventually to strokes and heart attacks. Several efficient drugs exist to decrease blood cholesterol levels, but are inefficient for treating familial hypercholesterolemia. Therefore new drugs must be developed. It was observed that inhibiting HDAC7 increased conversion of cholesterol into excreted bile acids by enhancing the activity of 7α-cholesterol hydroxylase, the rate-limiting enzyme in cholesterol catabolism. This represents a potential new strategy for decreasing cholesterol levels. The project was divided into two main parts: to understand and elucidate mechanisms underlying HDAC inhibitor isoform-specificity and to explore HDAC7-SMRT interaction as an alternative strategy of HDAC7 inhibition. Several protein engineering steps were carried out on HDAC7, using the ESPRIT technology. Crystallisation trials and inhibition tests were performed with a promising compound. This compound was derived from the pan-HDAC inhibitor SAHA, which was substituted in the meta positions of its phenyl cap. Crystallisation trails are ongoing with this compound. ESPRIT was applied as well on SMRT. The generated soluble fragments were tested for their interaction with HDAC7 by 15N-HSQC NMR. A interacting fragment was identified. This interaction was confirmed by fluorescence anisotropy and surface Plasmon resonance. NMR experiments are ongoing to assign residues involved in the interaction.
Source: HAL
Author: Danielle C. Desravines
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W222436611