Protease inhibitors were designed to mimic the transition state of the proteases actual substrates. A peptide linkage consisting of –NH-CO- is replaced by an hydroxyethylen group (-CH-CH(OH)-) which the protease is unable to cleave. HIV protease inhibitors fit the active site of the HIV aspartic protease and were rationally designed utilizing knowledge of the aspartyl proteases mode of action. The most promising transition state mimic was hydroxyethylamine  which led to the discovery of the first protease inhibitor, saquinavir. Following that discovery, other HIV protease inhibitors were designed using the same principle.