Protein silencing is an important aspect of both therapeutic targeting of aberrant protein activity and scientific investigation of native protein function. Many different techniques for silencing proteins at the DNA or RNA level exist, but new adaptable technologies are needed to effectively silence proteins at the post-translational level, and particularly with post-translational modification resolution. One such technology, developed by the DeLisa laboratory and termed ubiquibodies, hijacks natural cellular mechanisms to silence proteins post-translationally. A synthetic enzyme—the ubiquibody—functions by connecting two independent polypeptide domains, a target recognition domain and a catalytic domain via a flexible linker. This project has focused on mapping the tolerances of the ubiquibody technology. Expanding the range of silenced targets has been a key goal, as well as investigation into each of the three ubiquibody domains: target recognition, catalytic, and the linker between.