Case study: HIV‐1 protease inhibitors Background: Peptidomimetics describes the design of a compound that imitates the activity and appearance of a peptide while improving its bioavailability for oral delivery. Instructions: Read the passage below about the development of HIV‐1 protease inhibitors. Learning Goal: To see the challenges of developing an oral drug based on a peptide lead. HIV‐1 protease cleaves peptide chains, so its natural substrate is a peptide. Early x‐ray crystallographic data on HIV‐1 protease showed a handful of important hydrophobic and hydrogen bonding interactions between the substrate and enzyme. Based off this information, researchers at Abbott reported in 1994 a pseudopeptide, compound A74704 (1), with low nanomolar inhibitory activity. Compound 1 preserved the key interactions of the native substrate in part by allowing the inclusion of a water molecule in the binding pocket.1,2
Within five years three HIV‐1 protease inhibitors were approved by the US FDA. Ritonavir (2) from Abbott and saquinavir (3) from Roche were approved first, and amprenavir (4) from GlaxoSmithKline appeared a few years later. Both ritonavir and saquinavir retain some peptide character and even contain an amino acid residue. Amprenavir, on the other hand, is a true peptidomimetic with no amide linkages or amino acid residues. All three compounds have visual similarities, especially their common reliance upon CH2Ph and isopropyl side chains.