Aspartic Protease Inhibitors

Another class of proteases are the aspartic proteases. They have two opposing aspartate residues in their catalytic cleavage site. A water molecule located at the tip between the two aspartates is polarized. It nucleophilically attacks the carbonyl carbon of the amide bond to be cleaved. The cleavage reaction proceeds through a tetrahedral transition state in which a transient geminal diol structure is formed. Peptidomimetic inhibitors mimic this intermediate structure by using chemically stable building blocks. In particular, hydroxyl groups embedded in hydroxyethylene or statin moieties have been used as isosteres of the transition state. Aspartic proteases often cleave between hydrophobic amino acids. On either side of the cleavage site, these residues cannot form strong interactions with the specificity pockets of the protease, so the pockets are well established on both sides. Renin specifically cleaves angiotensinogen to angiotensin I. This product is then further cleaved to the octapeptide angiotensin II, which increases blood pressure upon recognition at its receptor. Renin has a large, nearly fused S1/S3 pocket. This led to the design concept of bridging the P1/P3 substituents in the inhibitor aliskiren and disrupting its central peptide chain. The result was a more polar, orally available antihypertensive with a good duration of action. HIV protease is a viral aspartic protease. It cleaves the initial polypeptide chain into mature proteins required for the life cycle of the virus. It is a C2-symmetric homodimer. A structural water molecule mediates interactions between the bound substrates and the flap region that closes the catalytic site. By systematic variation of the minimal substrate and introduction of transition state isosters, a series of potent and selective drugs with peptide-like scaffolds have been developed for therapy. Upon administration, the virus becomes resistant through mutational changes. Exchanges at almost half of all amino acid positions have been reported. Combined antiretroviral therapy (HAART) is recommended for HIV infection and attempts to achieve better suppression of viral replication by administering multiple inhibitors that act on different viral target proteins. In addition to renin and HIV protease, cathepsin D, β- and γ-secretase, the parasitic plasmepsin proteases, and the fungal secretory aspartic protease SAP have been investigated as potential drug targets. https://sn.pub/wrrga8