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Selection of Effective HTRA3 Activators Using Combinatorial Chemistry
Magdalena Wysocka1, Kamila Sychowska1, Natalia Gruba1
1Faculty of Chemistry, University of Gdansk , PL80952 Gdansk, Poland.
ACS Combinatorial Science
|July 26, 2017
Summary
Researchers developed peptidomimetics that significantly enhance the proteolytic activity of high temperature requirement A (HtrA3) protease. These compounds selectively increase HtrA3 protease activity, offering potential therapeutic applications.
Area of Science:
- Biochemistry
- Enzymology
- Medicinal Chemistry
Background:
- The high temperature requirement A (HtrA3) protease plays a role in cellular protein homeostasis.
- Modulating HtrA3 protease activity is a potential therapeutic strategy for various diseases.
Purpose of the Study:
- To identify and synthesize novel compounds that can activate the proteolytic activity of HtrA3 protease.
- To evaluate the efficacy and selectivity of these activators.
Main Methods:
- Synthesis of a peptidomimetic library.
- Enzymatic evaluation of synthesized compounds using an artificial HtrA3 substrate.
- Iterative deconvolution in solution to identify potent activators.
- Molecular modeling to understand binding interactions.
Main Results:
- Two potent HtrA3 activators were identified, functioning in the micromolar range.
- The selected compounds demonstrated over 40-fold selective increase in HtrA3-mediated proteolysis.
- Molecular modeling indicated strong binding of the activators to the PDZ domain of HtrA3.
Conclusions:
- Novel peptidomimetics effectively activate HtrA3 protease activity.
- These activators exhibit selectivity and potentiation of proteolysis.
- The findings provide a basis for developing HtrA3-targeted therapeutics.
