Pepstatin analogs

Table I. Inhibition of Aspartyl Proteases by Pepstatin Analogs... 

We synthesized the ketomethylene, , and hydroxyethylene,8, isosteres of a Leu-Ala dipeptide sequence in order to explore the importance of the two extra atoms in statine relative either to substrate or to the tetrahedral intermediate (Figure 1) in another aspartyl protease system. The compounds were synthesized by the routes outlined in Scheme I. This route was chosen so as to provide steric control at C-2 and C-5 of both 7 and 8 as well as to provide ready access to C-4 labeled analogs. Details of the synthesis have been described else-where.(23.24) Inhibitors were synthesized in which Leu-Ala dipeptide Isosteres replaced either Sta or Sta-Ala in known pepstatin analogs. Inhibition of porcine pepsin was determined using the reported spectrophotometric assay (Table I).(25)... 

S,4S)-4,8-Diamino-3-hydroxyoctanoic acid (DAHOA) derivatives were synthesized by the route shown in Scheme II using the known aldehyde Boc-Lys(Z)-CH0 (29) and were converted to the DAHOA peptide analogs shown. Inhibition of penicillopepsin by all statine and DAHOA pepstatin analogs was measured using substrate 21. The results of these determinations are shown in Table I. 

Nisato, D., Wagnon, J., Callet, G., et al. (1987) Renin inhibitors. Free-Wilson and correlation analysis of the inhibitory potency of a series of pepstatin analogs on plasma renin. J Med Chem 30(12), 2287-2291. 

Interestingly, it was reported that the synthesis of Fe(C5H4-CO-Pro,-OBn)2 with n= 2,3 or4, yielded a second class of compounds, i.e. the incomplete substituted derivatives Fe(C5H4-CO-Pro,j-OBn)(C5H4-CO-OBt) [26]. In a subsequent paper, Kraatz and coworkers reacted the incompletely substituted derivatives with n = 3 and 4 with a pepstatin analog to obtain the conjugates shown in Scheme 5.6 [28]. 

Thus, although pepstatin still may be considered a transition-state analog inhibitor owing to the tetrahedral geometry at C-3 of statine, pepstatin is also a collected-... 

Pepstatin A aspartic proteases competitive, transition state analog class-specific sub-nanomolar (18)... 

Figure 7 Various transition-state protease inhibitors. Bortezomib is an approved drug for the treatment of multiple myeloma. It is a boronic acid analog that inhibits the proteosome, a threonine protease. The boronic acid moiety can adopt a tetrahedral conformation in the active site. Pepstatin is a peptidyl aspartic acid inhibitor. The reactive statine group binds to the catalytic machinery, and the chiral hydroxyl group of the statine mimics the tetrahedral geometry of the transition state. Idinavir is an approved HIV 1 Protease inhibitor that binds to the active site via a hydroxyethylene transition state isostere. Aldehydes are also transition state analogs, which are susceptible to nucleophilic attack. In cysteine, serine and threonine proteases, this results in a covalent, reversible inhibition mechanism.

In 1985 Toh et recognized a sequence in the Rous sarcoma virus (RSV) genome that resembled that of the Asp-Thr-Gly motif of aspartic proteinases, and a similar sequence was subsequently identified in HIV. This led to the suggestion that retroviruses contained a dimer which resembled the putative dimeric ancestor of the pepsin-like aspartic proteinases.The analogy, supported by observations that an HTV proteinase was sensistive to pepstatin, led to interest in the development of HIV proteinase inhibitors. It was later noted that HIV requires a specific protease for the maturation of its components and therefore inhibition of this protease could represent a therapeutic approach to the treatment of AIDs. 

---