Small-molecule inhibitor: ritonavir

Name

History: The history of the discovery of ritonavir in the mid-1990"s was described by Kempf et al. (1998) and Wlodawer & Vondrasek (1998).
Peptidases inhibited: Ritonavir is a highly selective inhibitor of the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively). Very low nanomolar K_i values are obtained with retropepsins that have not evolved resistance. In comparison, 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). There is slight cross-inhibition of peptidases in family A1 such as candidapepsin and pepsin (Gruber et al., 1999). Ritonavir inhibits plasmepsin-2 and plasmepsin-4 (Andrews et al., 2006). There are reports of modification of peptidase activities of the proteasome (T01.010, T01.011, T01.012) by ritonavir (Schmidtke et al., 2000). Inhibits cytochrome P450 3A (CYP3A), slowing the metabolism of other retropepsin inhibitors (von Moltke et al., 2000).
Mechanism: Inhibition is reversible. Crystal structures of complexes with retropepsin have been described by Kempf et al. (1997) and Clemente et al. (2004).
Pharmaceutical relevance: Ritonavir (Abbott) has been an important drug in the management of HIV (Arribas et al., 2005; Kaplan & Hicks, 2005).
DrugBank: DB00503

CID at PubChem: 392622
ChEBI: 193797
Structure
Chemical/biochemical name: 1,3-thiazol-5-ylmethyl [[3-hydroxy-5-[[3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]- butanoyl]amino]-1,6-diphenyl-hexan-2-yl]amino]formate
Formula weight: 721
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 ritonavir and saquinavir (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: Kempf et al. (1998); Wlodawer & Vondrasek (1998)