Zymogens are inactive enzyme precursors that must be proteolytically cleaved to manifest their catalytic activity. Enzyme precursors allow selective activation, minimizing the potential for enzymes to be destructive. Zymogens are typical for proteases, enzymes that cleave proteins. Many disease states, including cancer and HIV, involve proteases, such as matrix metalloproteases and caspases. Native zymogens have yet to be discovered for ribonucleases, the enzymes that form the basis for the EVade™ Ribonucleases.
The therapeutic potential of EVade™ ribonucleases may be extended
by development of a ribonuclease zymogen which is activated
at the site of disease. Such an enzyme could be constructed
by blocking the active site of the ribonuclease with a specific
peptide sequence that is cleaved by a disease-related protease.
The active site would be exposed once the ribonuclease encountered
the protease, resulting in a functional enzyme. In the absence
of the protease, the ribonuclease would remain inactive, protecting
normal cells from destruction.
To create a zymogen, the native C- and N-termini of were joined by a peptide containing the recognition sequence for an aspartyl protease. A ribonuclease zymogen was created that displayed: (1) high ribonucleolytic activity after proteolytic activation, (2) minimal, if any, enzymatic activity prior to activation, and (3) high intrinsic stability. The ribonuclease zymogens are being developed in a variety of areas.
A ribonuclease zymogen has been produced that was activated in the presence of the NS3 protease of the hepatitis C virus.
Quintessence Biosciences is interested in talking with partners for proteolytically activated therapeutics.
R.J. Johnson, S.R. Lin, R.T. Raines (2006) A ribonuclease zymogen activated by the NS3 protease of the hepatitis C virus. FEBS Journal 273, 5457 - 5465.
P. Plainkum, S. M. Fuchs, S. Wiyakrutta, R.T. Raines (2003) Creation of a Zymogen. Nature Structural Biology 10, 115-119.