Small-molecule inhibitor: nelfinavir

Name

History: Nelfinavir was described (as AG1343) by Longer et al. (1995). The early work on the development of nelfinavir were reviewed by Wlodawer & Vondrasek (1998).
Peptidases inhibited: Inhibits the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively). Variants of retropepsin that are resistant to nelfinavir may be sensitive to other inhibitors, and vice versa (de Mendoza et al., 2004; Svedhem et al., 2005). Does not inhibit porcine endogenous retrovirus retropepsin: Qari et al., 2001) or candidapepsins (e.g. A01.014: Pichová et al., 2001).
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: FDA-approved (Agouron Pharmaceuticals), and was the first of the retropepsin inhibitors to be approved for pediatric AIDS. The place of nelfinavir in the treatment of AIDS has been reviewed by Perry et al. (2005).
DrugBank: DB00220

CID at PubChem: 64143
ChEBI: 289082
Structure
Chemical/biochemical name: (3S,4aS,8aS)-2-[(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methyl-benzoyl)amino]-4-phenylsulfanyl-butyl]-N-tert-butyl- 3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-3-carboxamide
Formula weight: 568
Related inhibitors: Compounds L-682,679, L-685,434, AG-1002 and AG-1004 were intermediates in the design of indinavir and nelfinavir (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).
Reviews: Wlodawer & Vondrasek (1998)