Selectivity profiling of DegP substrates and inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Protein quality control is crucial for cellular health, and its dysfunction is linked to diseases like amyloidosis.
• Bacterial protein quality control factors, such as the serine protease DegP, are potential drug targets due to their role in pathogenesis.
• Current knowledge of DegP modulators is limited, with only a weak synthetic peptide substrate and no known inhibitors.

Purpose of the Study:

• To identify novel small molecule modulators for the bacterial serine protease DegP.
• To characterize the substrate specificity and inhibitory potential of new DegP-targeting compounds.
• To explore DegP as a potential drug target for bacterial infections and protein misfolding diseases.

Main Methods:

• Development and screening of a potent heptameric pNA-substrate for DegP activity.
• Synthesis and evaluation of chloromethyl ketone-based inhibitors targeting DegP.
• Specificity profiling of identified compounds against related proteases like subtilisin and elastase.

Main Results:

• Identification of a highly effective heptameric pNA-substrate for DegP.
• Discovery of potent chloromethyl ketone-based inhibitors specific for DegP.
• Characterization of specific substrates and inhibitors for subtilisin and elastase, demonstrating broad protease profiling.

Conclusions:

• The identified substrates and inhibitors provide valuable tools for studying DegP function and its role in bacterial virulence.
• DegP represents a promising drug target, and the developed modulators offer a foundation for novel therapeutic strategies.
• This work expands the repertoire of chemical tools for investigating HtrA protease family members and their physiological roles.