Strategies for Designing Drugs that Target the Sir2 Family of Enzymes to Treat Multiple Diseases

Sir2 enzymes comprise a unique class of NAD+ -dependant protein deacetylases that are involved in a broad range of biological processes including transcriptional silencing, aging, fat mobilization and regulation of the p53 tumor suppressor gene. The Sir2 proteins catalyze NAD+ -dependant acetylation of lysine at the critical site known as the C-pocket, releasing the deacetylated peptide, nicotinamide, and O-acetyl ADP-ribose. A part of the C-pocket is formed by the flexible loop region that adopts a variety of conformations depending upon substrate and inhibitor binding. JHU researchers have recently put forth an invention to screen for small molecules or proteins designed to target the flexible loop that could be used to modulate enzyme activity, either repressing or stimulating the deacetylation reaction or modulating nicotinamide inhibition. This differs from the more traditional approach to screening for molecules that bind within the enzyme active site. Description (Set) Proposed Use (Set) This technology provides a new and targeted way to identify both agonists and inhibitors of Sir2 activity. Enzymes agonists in particular are exceedingly rare, yet there are a number of human diseases that could be treated if one could stimulate- rather than inhibit- Sir2 enzyme activity. Stimulation of Sir2 enzymes has been shown to slow replicative aging, and Sir2 agonists are therefore plausible drugs for treating age-related degeneration. Also, Sir2 enzymes are attractive drug targets because of their involvement in diabetes, inflammation, and regulation of p53.

Inventor(s): Wolberger, Cynthia

Type of Offer: Licensing

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