Design of Novel Molecules that Regulate Sirtuins

Inventors: Ronen Marmorstein and Brandi D. Sanders

Tech ID: MR07001

Description: Researchers at The Wistar Institute have identified and characterized a novel target binding site involved in regulating the activity of Sir2 proteins (or Sirtuins, the class III family of histone deacetylases, silent information regulator 2).  Sirtuins deacetylate numerous cell proteins, thereby stimulating diverse biological functions related to metabolism and cell growth.  Their activity has been linked to increased lifespan and calorie-associated effects on longevity.  Compounds that target Sirtuins show promise in the treatment of diabetes, and diseases of degeneration and aging.  Wistar scientists have identified and characterized a new molecular binding target, the nicotinamide binding site, which is expected to enable the development of new classes of small molecule Sirtuin modifiers.  Experimental studies have validated the role of this binding site in the regulation of Sirtuin activity.  Small-molecule compounds that target this site can act either as inhibitors of Sirtuins, or as effective Sirtuin activators, influencing a range of biological functions including DNA regulation, programmed cell death, neuronal protection, insulin signaling, and fat mobilization.   

Key Words: Sir2, Sirtuins, longevity, age-related disease, metabolic diseases, diabetes, rational drug design, nicotinamide

Applications and Advantages: This technology provides a method for rational, structure-aided drug design to develop small molecules that target the regulatory nicotinamide binding site of Sir2 proteins.  Sir2 modulators may be useful for the treatment of diabetes, obesity, Alzheimer’s, other neurodegenerative diseases, and diseases of aging.

Intellectual Property Status: U.S. Patent Application No. 12/023,287 (US-2008-0305496, published 12/11/2008); U.S. Patent Application No. 12/511,679 (US-2009-0326007, published 12/31/2009).

Licensing Opportunity: Wistar is seeking to collaborate with a corporate partner to use this technology to develop small molecule modulators of Sir2.  An exclusive license or sponsored research to further develop the technology would be considered.

Relevant Publication:  Sanders, B.D.; Zhao,K.; Slama, J.T.; Marmorstein, R.; (2007) “Structural basis for nicotinamide inhibition and base exchange in Sir2 enzymes”. Mol Cell 25: 463-472

Contact:

Meryle J. Melnicoff
Director, Business Development
The Wistar Institute
3601 Spruce Street
Philadelphia, PA 19104
Phone: (215) 898-0049
Fax: (215) 573-2456
melnicoff@wistar.org

Last updated: Nov. 2007