Prion diseases are characterized by the accumulation of a misfolded prion protein, PrPSc which derives from a posttranslational conformational change of the host-encoded cellular prion protein, PrPC. The process of the conformational transition remains enigmatic, but, regardless of the initiating event, PrPSc appears to act as a conformational template by which PrPC is converted to a new molecule of PrPSc through protein-protein interactions. From a medicinal chemistry point of view, protein-protein interactions have recently become attractive drug targets, and recent studies suggest that these interfaces may be amenable to inhibition also by small molecules. Nevertheless, the design of chemical entities able to target a specific protein-protein interaction remains challenging, probably because of the complexity of the recognition mechanism. To address such issues, the use of combinatorial chemical libraries based on small molecules holds promise as a powerful approach in the identification of novel lead compounds. We envisaged the planar 2,5-bis-diaminobenzoquinone scaffolds as a privileged motif in modulating protein-protein interactions. Therefore, we decided to attach seven aminoacids methyl esters to two different benzoquinone cores, generating a small combinatorial library of 14 derivatives, whose general structure is reported in the figure below. The selected residues span a reasonable range of size, polarity, aromaticity, and hydrogen-bonding capability. This might allow us an initial investigation of the chemical basis for small molecule inhibition of protein–protein interaction in prions.
M.L. Bolognesi, P. Carloni, G. Legname (2008). Design and synthesis of a library of benzoquinone derivatives as probes to modulate protein-protein interactions in prions. s.l : s.n.
Design and synthesis of a library of benzoquinone derivatives as probes to modulate protein-protein interactions in prions
BOLOGNESI, MARIA LAURA;
2008
Abstract
Prion diseases are characterized by the accumulation of a misfolded prion protein, PrPSc which derives from a posttranslational conformational change of the host-encoded cellular prion protein, PrPC. The process of the conformational transition remains enigmatic, but, regardless of the initiating event, PrPSc appears to act as a conformational template by which PrPC is converted to a new molecule of PrPSc through protein-protein interactions. From a medicinal chemistry point of view, protein-protein interactions have recently become attractive drug targets, and recent studies suggest that these interfaces may be amenable to inhibition also by small molecules. Nevertheless, the design of chemical entities able to target a specific protein-protein interaction remains challenging, probably because of the complexity of the recognition mechanism. To address such issues, the use of combinatorial chemical libraries based on small molecules holds promise as a powerful approach in the identification of novel lead compounds. We envisaged the planar 2,5-bis-diaminobenzoquinone scaffolds as a privileged motif in modulating protein-protein interactions. Therefore, we decided to attach seven aminoacids methyl esters to two different benzoquinone cores, generating a small combinatorial library of 14 derivatives, whose general structure is reported in the figure below. The selected residues span a reasonable range of size, polarity, aromaticity, and hydrogen-bonding capability. This might allow us an initial investigation of the chemical basis for small molecule inhibition of protein–protein interaction in prions.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.