Inhibition of proteolysis and other posttranslational modifications with substrate-targeted inhibitors

This article reviews the concept of developing protease inhibitors that target the substrate polypeptide rather than the enzyme. Substrate-targeted inhibitors have the potential to be more specific than even the most highly selective enzyme-targeted inhibitors because essentially all proteases process multiple substrates. The challenge in developing substrate-targeted protease inhibitors centers on the development of high-affinity binding agents for short stretches of amino acids (linear epitopes). Recent experimental progress toward this goal and a number of other potential solutions are discussed.