Small-molecule inhibitor: saquinavir

Name

History: Saquinavir, described by Roberts et al. (1990) was the first inhibitor of the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively) to be approved by the FDA. The successful design was based on the realisation that the retropepsins are able to hydrolyse -TyrPro- and -PhePro- bonds, for which the mammalian aspartic peptidases such as pepsin and cathepsin D have little affinity. The analogue of proline used as P1" residue in saquinavir is (S,S,S)-decahydroisoquinoline-3-carbonyl, and the peptide isostere is the hydroxyethylamine moiety.
Peptidases inhibited: Primarily viral aspartic peptidases in family A2, but there is some activity against other aspartic peptidases including candidapepsin: Korting et al., 1999). The retropepsins rapidly evolve drug-resistance in treated patients, and sequence variants differ greatly in susceptibility to inhibition. Inhibition of the retropepsin of human endogenous retrovirus is weak (Towler et al., 1998) and that of porcine endogenous retrovirus retropepsin is negligible (Qari et al., 2001). Saquinavir inhibits plasmepsin-2 and plasmepsin-4 (Andrews et al., 2006).
Mechanism: Inhibition is reversible, normally with low nanomolar K_i values. The structure of the complex has been shown by Krohn et al. (1991).
Pharmaceutical relevance: Saquinavir is approved for drug use (Hoffman-La Roche).
DrugBank: DB01232

CID at PubChem: 60934
ChEBI: 171934
Structure
Chemical/biochemical name: (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1- phenyl-butan-2-yl]-2-(quinoline- 2-carbonylamino)butanediamide
Formula weight: 767
Related inhibitors: A-117673 is the D-valinyl diastereomer of ritonavir. Compounds Ro 31-8588, A-74704, A-75925, A-77003 and A-80987 were intermediates in the design of saquinavir and ritonavir (Wlodawer & Vondrasek, 1998).

Inhibitor class: This compound is of the peptide isostere class of aspartic peptidase inhibitors. The discovery of pepstatin drew attention to the fact that structural analogues of the scissile bond that are not hydrolysable but mimic the transition state in catalysis can be potent reversible inhibitors of peptidases. Development of such inhibitors for aspartic peptidases was driven by the need for drugs against AIDS (Roberts et al., 1990). Structural analogues of the peptide bond that have been used include hydroxyethylene, difluorostatone, statine, phosphinate and reduced amide. It was found that pepstatin inhibits retropepsin (Seelmeier et al., 1988; Richards et al., 1989), but there was a need for potent inhbitors of retropepsin that would not interact with mammalian aspartic peptidases such as pepsin. A key development was the discovery that retropepsins have the unusual ability to cleave bonds with S1" proline, and it was discovered that proline could be replaced by analogues such as pipecolic acid in inhibitors (Copeland et al., 1990).The development of such inhibitors as drugs, and the contribution that structure-based drug design has made to it, have been lucidly reviewed by Wlodawer and colleagues (Wlodawer & Erickson, 1993; Wlodawer & Vondrasek, 1998).