Small Molecule Protease Inhibitors as Model Peptidomimetics

Proteases constitute one of the largest sub-classes of enzymes, accounting for ca. 2% of the proteins encoded in the human genome. They play a key role in protein degradation and signaling, regulating a variety of physiological processes. Dysregulation of their activity is associated with various pathological conditions like cancer, neurodegenerative disorders, inflammatory or cardiovascular diseases. Protease activity can be controlled by regulating enzyme concentrations, but also by inhibitors, molecules that modulate enzyme function, inspiring the development of small molecule protease inhibitors for therapeutic purposes. Protease inhibitors can be designed from the corresponding substrates by isostere replacement at the scissile bond. This process yields a first-generation of inhibitors that usually exhibit poor drug-like profiles that need subsequently be improved to generate a second-generation, by smoothing their peptide-like features. This process is reviewed in the present report and exemplified in the successful discovery stories of different inhibitors that correspond to four types of proteases, including the angiotensin converting enzyme (metalloprotease); HIV protease (aspartate protease); thrombin (serine protease) and the proteasome (threonine protease). A detailed description of the stories behind their design from their initial discovery to the final product is described in this report. Moreover, despite successful discovery stories, the challenges associated with designing novel protease inhibitors are examined. Finally, the relevance of these drugs in the present drug market is also reported.