Ruthenium-based caging of nitrile-containing enzyme inhibitors

Case ID:

Technology Summary:
Novel synthesis methods for caging nitrile-containing bioactive molecules to a non-toxic ruthenium metal complex have been developed which enable light activated release of a cathespin K inhibitor. Numerous potent and selective cathepsin inhibitors are being developed as drug candidates. Cysteine cathepsins are involved in the pathophysiology of diseases such as osteoporosis, autoimmune disorders, and cancer.  Using the method developed at WSU, in vitro studies confirmed light activated inhibition of the cysteine protease papain in series of human cell lysates and cultured macrophages with an IC50 values 32X greater compared to the dark compound. This invention enables control of activation and localized delivery of such inhibitors.

• Reaction dynamics
• Spatial localization
• Photodynamic therapy

Notably, the synthesis method developed can be applied to numerous nitrile containing molecules. Effective caging with RuII(bpy)2 moiety has been shown for numerous R-CN groups including Me-CN, the compound test below and the cathepsin K inhibitor Odanacatib (Merck). The complexes are stable in powder form and under red light in aqueous solutions. Minimal side-effects are predicted in vivo based on the nature of the Ru(II) metal center used and unlike photo-activated crosslinking or oxidation based methods there is no irreversible damage to the proteins involved in this method of inhibition.  Visible light can be used to trigger the release to provide spatial and kinetic control over enzyme inhibition.

Stage of Development: Pre-clinical
• Minimal cyto-toxicity (MTT assay)

References:  “Light Activation of a Cysteine Protease Inhibitor: Caging of a Peptidomimetic Nitrile with RuII(bpy)2” T. Respondek et al.  J. Am. Chem. Soc., 2011, 133, p17164-17167

Patent Status: Issued, 9,593,138

Patent Information:
For Information, Contact:
Robert Olson
Wayne State University
Jeremy Kodanko
Claudia Turro