Biomimetic selenocystine based dynamic combinatorial chemistry for thiol-disulfide exchange

Area of Science:

• Biochemistry
• Chemical Biology
• Medicinal Chemistry

Background:

• Dynamic combinatorial chemistry (DCC) is crucial for biological applications but often requires slow thiol-disulfide exchange kinetics.
• Achieving efficient exchange chemistry under physiological conditions (pH, temperature) remains a challenge for DCC.

Purpose of the Study:

• To identify a catalyst that accelerates thiol-disulfide exchange under physiological conditions.
• To broaden the applicability of DCC in biological environments, including protein folding and self-assembly.
• To explore DCC for identifying inhibitors using enzyme-templated approaches.

Main Methods:

• Investigated selenocystine as a catalyst for thiol-disulfide exchange reactions.
• Assessed the catalytic activity of selenocystine at physiological pH and low temperatures.
• Applied DCC for target-driven self-assembly using spermine, spermidine, and NADPH as templates with glucose oxidase as a mold.
• Identified inhibitors using a glucose oxidase-directed DCC library.

Main Results:

• Selenocystine significantly accelerates slow thiol-disulfide exchange systems.
• Selenocystine promotes the correct folding of scrambled RNase A enzyme.
• The study demonstrates DCC's utility in identifying non-competitive inhibitors for glucose oxidase.
• Catalytic acceleration broadens the practical pH range for oxidative protein folding.

Conclusions:

• Selenocystine effectively catalyzes thiol-disulfide exchange, mimicking natural strategies for biological applications.
• The findings expand the utility of DCC in biological systems, particularly for protein folding and inhibitor discovery.
• This work provides a new catalytic approach for accelerating DCC under physiological conditions.