Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.

Structural basis of sirtuin 6 activation by synthetic small molecules / You, W; Rotili, Dante; Li, Tm; Kambach, C; Meleshin, M; Schutkowski, M; Chua, Kf; Mai, Antonello; Steegborn, C. 1.. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - STAMPA. - 56:(2017), pp. 1007-1011. [10.1002/anie.201610082]

Structural basis of sirtuin 6 activation by synthetic small molecules.

ROTILI, Dante;MAI, Antonello
;
2017

Abstract

Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.
2017
deacetylases; drug discovery; enzymes; sirtuin activators; structural biology
01 Pubblicazione su rivista::01a Articolo in rivista
Structural basis of sirtuin 6 activation by synthetic small molecules / You, W; Rotili, Dante; Li, Tm; Kambach, C; Meleshin, M; Schutkowski, M; Chua, Kf; Mai, Antonello; Steegborn, C. 1.. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - STAMPA. - 56:(2017), pp. 1007-1011. [10.1002/anie.201610082]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/944091
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