LifeSensors, Inc., a biotech company developing cutting-edge technologies for studying the ubiquitin pathway, has been awarded a U.S. patent for the development of novel, fluorescent di- and poly-ubiquitin deubiquitinase (DUB) substrates (US 8,518,660). DUBs, which remove ubiquitin from human proteins, are important targets for drug discovery in a number of therapeutic areas and optimal DUB substrates are essential for these efforts.
Utilizing internally quenched fluorescence (IQF) technology, the patented substrates provide for the sensitive detection of deubiquitinating enzyme activity on ubiquitin chains with specific lysine linkages. Other available deubiquitinase substrates measure cleavage of linear peptide or amide bonds. The IQF- polyubiquitins, however, are conjugated via true isopeptide bonds and serve as more physiologically relevant enzyme targets. “These IQF-DiUbTM substrates create opportunities for improved measurement of physiologically relevant deubiquitylase activity for basic research and drug discovery,” according to Dr. James Strickler, Vice President of Research and Development at LifeSensors.
Ubiquitination, a post-translational modification, has been shown to play important roles in almost every aspect of physiology including cell growth and differentiation, inflammation, apoptosis, DNA repair, muscle and neuronal degeneration, and viral infection. Consequently, the imbalances between ubiquitination and deubiquitination of protein targets has been linked to several diseases in each of these areas. Ubiquitination is carried out by enzymes called ubiquitin ligases, while deubiquitination occurs by the highly specific activity of DUBs, which recognize both ubiquitin and the isopeptide bond. The inhibition or activation of DUBs is increasingly being explored for new drug development thereby creating a growing need for sensitive, reproducible substrates that can measure true isopeptidase activity as well as be supplied in quantities that can be used in high throughput formats.