Abstract
Dynamic combinatorial chemistry applied to biological environments requires the exchange chemistry of choice to take place under physiological conditions. Thiol-disulfide exchange, one of the most popular dynamic combinatorial chemistries, usually needs long equilibration times to reach the required equilibrium composition. Here we report selenocystine as a catalyst mimicking Nature’s strategy to accelerate thiol-disulfide exchange at physiological pH and low temperatures. Selenocystine is able to accelerate slow thiol-disulfide systems and to promote the correct folding of an scrambled RNase A enzyme, thus broadening the practical range of pH conditions for oxidative folding. Additionally, dynamic combinatorial chemistry target-driven self-assembly processes are tested using spermine, spermidine and NADPH (casting) and glucose oxidase (molding). A non-competitive inhibitor is identified in the glucose oxidase directed dynamic combinatorial library.
Highlights
Dynamic combinatorial chemistry applied to biological environments requires the exchange chemistry of choice to take place under physiological conditions
We are interested in the application of Dynamic combinatorial chemistry (DCC) systems or Dynamic combinatorial libraries (DCLs) to biological environments where a protein or a biomolecule directs the assembly of the building blocks at dynamic equilibrium towards the synthesis of the best ligand or synthetic receptor in situ
Having established that Secox is an effective promoter for thiol/disulfide exchange, we studied the introduction of the enzyme glucose oxidase (GOx) to the DCL
Summary
Dynamic combinatorial chemistry applied to biological environments requires the exchange chemistry of choice to take place under physiological conditions. Thiol-disulfide exchange, one of the most popular dynamic combinatorial chemistries, usually needs long equilibration times to reach the required equilibrium composition. Disulfide exchange is considered one of the most popular dynamic covalent chemistries applied to biological systems This dynamic process is based on the thiol–disulfide equilibrium where the slow oxidation of the thiols competes with the disulfide exchange in aqueous solutions. Even though disulfide exchange proceeds smoothly at neutral or slightly basic pH, it usually requires several days to reach the required equilibrium12,13 To improve this limitation, several reaction conditions based on the use of a co-solvent such as DMSO14, glutathione redox buffer, and high concentrations of selenol derivatives have been reported as alternative additives to speed up the exchange reaction from weeks to days. Selenium acts as a nucleophile initially attacking the disulfide bond of Trx (Fig. 1a), or as an electrophile accepting electrons from the redox center of TrxR as part of the selenosulfide bond (Fig. 1b)
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