Small-molecule inhibitor: OM99-2

Name

History: On the basis of an octapeptide substrate of memapsin-2, Glu-Val-Asn-Leu-Ala-Ala-Glu-Phe (Ermolieff et al., 2000), Tang and co-workers designed an inhibitor by replacing the Leu-Ala peptide bond with an hydroxyethylene transition-state isostere. The structure of the complex of the inhibitor (OM99-2) with the enzyme was described by Hong et al. (2000).
Peptidases inhibited: Memapsin-2 is inhibited with K_i = 2 nM.
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Memapsin-2 (also called BACE) is a target for control of Alzheimer"s disease, and inhibitors of the peptidase are therefore potential leads to important drugs (Guo et al., 2006). Being a large, peptidic molecule, OM99-2 itself does not have the right characteristics for a drug.

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).