The development of protein-directed DCC has not been straightforward because the reversible reactions employed must occur in aqueous solution at biological pH and temperature, and the components of the DCL must be compatible with proteins.
Several reversible reactions have been proposed and/or applied in protein-directed DCC. These included boronate ester formation, diselenides-disulfides exchange, disulphide formation, hemithiolacetal formation, hydrazone formation, imine formation and thiol-enone exchange.