Small-molecule inhibitor: atazanavir

Name

History: As BMS-232632, atazanavir was described by Robinson et al. (2000).
Peptidases inhibited: An inhibitor of the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively).
Mechanism: Inhibition is reversible, normally with low nanomolar K_i values. Substitution of leucine for isoleucine at residue 50 (I50L) of HIV-1 retropepsin produces an atazanavir-specific resistance, but increased susceptibility to most other approved retropepsin inhibitors (Weinheimer et al., 2005).
Pharmaceutical relevance: FDA-approved for drug use.
DrugBank: DB01072

CID at PubChem: 148192
ChEBI: 37924
Structure
Chemical/biochemical name: [1-[[3-hydroxy-4-[(2-methoxycarbonylamino-3,3-dimethyl-butanoyl)amino-[(4-pyridin-2-ylphenyl)methyl]amino]-1-phenyl-butan-2- yl]carbamoyl]-2,2-dimethyl-propyl]aminoformate
Formula weight: 705

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: An azapeptide compound.