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Structure-based development of novel sirtuin inhibitors.

Christine Schlicker¹, Gina Boanca, Mahadevan Lakshminarasimhan

¹Department of Biophysics, Ruhr-University Bochum, Germany.

|September 23, 2011

Summary

Researchers developed structure-based methods to create isoform-specific sirtuin inhibitors. This approach identified potent, highly specific Sirt2 inhibitors, advancing the development of targeted therapies for aging and metabolic diseases.

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Area of Science:

Biochemistry
Molecular Biology
Pharmacology

Background:

Sirtuins are crucial NAD+-dependent deacetylases regulating metabolism, stress, and aging.
Seven mammalian sirtuin isoforms (Sirt1-7) exist, each with unique localization and substrates.
Sirtuins are therapeutic targets for metabolic and aging-related diseases.

Purpose of the Study:

To develop isoform-specific small-molecule inhibitors for human sirtuins.
To exploit available sirtuin crystal structures for inhibitor design.
To identify novel therapeutic strategies targeting sirtuin pathways.

Main Methods:

Virtual docking of a compound library into crystal structures of Sirt2, Sirt3, Sirt5, and Sirt6.
Activity assays to characterize compound potency and isoform specificity.
Structure comparison to identify key binding interactions for specificity.

Main Results:

Identified compounds with varying degrees of sirtuin isoform specificity.
Discovered two compounds with micromolar potency and high specificity for Sirt2.
Characterized a novel binding pocket extending from the peptide-binding groove as a target for specificity.

Conclusions:

A structure-based, family-wide approach can yield potent, isoform-specific sirtuin inhibitors.
Identified Sirt2-specific inhibitors and lead structures for further drug development.
This strategy is crucial for developing a comprehensive panel of isoform-specific sirtuin modulators.