Speeding up thiol-disulfide molecular networks

This is the story behind the paper "Biomimetic selenocystine based dynamic combinatorial chemistry for thiol-disulfide exchange"

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Being a chemist working in a Biological research center has many advantages. It’s like learning a new language doing a Language Immersion Program in a native speaking country. Sometimes you can feel a little bit lost, but it certainly helps build up research at the interface of chemistry and biology by exposing yourself to research outside your specialty.

This work started with a seminar we attended about a filament protein involved in cell division and redox sensing. At this time, we were exploring thiol-disulfide systems from the chemical point of view. We have just started to set up a Protein-directed dynamic combinatorial chemistry library. It took more than two days to equilibrate, and we could not preserve the protein stability for that long. We tried reported catalysts used by chemists and some of the reagents mentioned in this seminar to speed the thiol-disulfide exchange, but unfortunately, nothing worked. So, we started wondering how Nature did it. Diving into literature, we became fascinated with the Thioredoxin system and selenoenzymes. It was brilliant how the replacement of S for Se worked. It caught our attention one of the intermediate reactions in the mechanism, the formation of S-Se bond. We tested selenocystine (Secox) and verified that the addition of a small percentage of Secox accelerated up to 20 times the thiol-disulfide reaction. Since we are interested in dynamic combinatorial chemistry, we tested the benefits of Secox to thiol-disulfide exchange in the absence and the presence of different templates with excellent results. The addition of Secox did not interfere with several recognition processes. And this is how this work started growing and growing. Next, we challenged ourselves to target a protein template, glucose oxidase, and to adapt glucose oxidase enzymatic activity tests protocol to a microplate reader to study the mechanism of action of the inhibitors discovered. We finally assayed the efficiency of Secox on protein folding, especially on scrambled RNase A disulfide bond isomerization, and again Secox showed its potential under different conditions. From a chemical and biological perspective, it’s a molecule worth to try!