Small-molecule inhibitor: kynostatin-272

Name

History: Kynostatin-272 was described as a retropepsin inhibitor by Mimoto et al. (1992).
Peptidases inhibited: Inhibits the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively). Rous sarcoma virus retropepsin is resistant unless mutated (Ridky et al., 1996).
Mechanism: Inhibition is reversible, normally with low nanomolar K_i values. The structure of enzyme/inhibitor complexes has been reported (Baldwin et al., 1995).

CID at PubChem: 60927
Structure
Chemical/biochemical name: (4R)-3-[(2S,3S)-2-hydroxy-3-[[(2R)-2-[(2-isoquinolin-5-yloxyacetyl)amino]-3-methylsulfanyl-propanoyl]amino]-4-phenyl-butanoyl]- N-tert-butyl-thiazolidine-4-carboxamide
Formula weight: 668

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).
Comment: Kynostatin-272 contains allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] - thioproline as analogue of the substrate Phe-Pro moiety (Baldwin et al., 1995).