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February 01, 2009 (Vol. 29, No. 3)

Accelerating Protease Drug Development

Use of the REPLi FRET Peptide Library Facilitates Identification of Substrates

  • Proteases are involved in the regulation of a wide variety of essential physiological processes, and their dysregulation has been implicated in a number of disorders including cardiovascular disease, rheumatoid arthritis, Alzheimer’s disease, and cancer. Hence, proteases and their substrates are increasingly viewed as valuable drug targets in disease treatment. Given the large number of proteases in the human genome (>560), however, the task of characterizing the biological function in vivo of all proteases, including the identification of all protease substrates, is daunting.  

    Information relating to the specific residue requirements spanning the protease cleavage site in peptide substrates is invaluable in assisting the development of specific inhibitors and in identifying possible in vivo protein substrates. In addition, specificity information can be used to design highly sensitive and specific synthetic fluorogenic substrates and these in turn enable screening of compounds to identify small molecule inhibitors.

    As a result, there is an urgent need for more rapid techniques of substrate discovery on a system-wide basis, with the capability of identifying new protease substrates directly from cells, tissues, and body fluids, and quantitating differences in substrate processing of low-abundant proteins as disease markers.

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