Statine dipeptide analog

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)... 

In summary, the results with pepsin extend the renin data reported by Szelke and Boger and strongly support the postulate of Boger that statine is an analog of a dipeptide tetrahedral intermediate.(20) The C-3 hydroxyl group hydrogen bonds to Asp-213 (220) and Asp-33(35) and displaces a "bound" water molecule from the active site. The isobutyl side chain of statine corresponds to the PI substituent that binds to the SI subsite on the enzyme. The C-1 and C-2 atoms of statine serve to span... 

Simulated annealing has also been applied to the conformational study of dipeptide models of Gly, Ala, and Asp pentaglycine and Leu-enkephalin [11] an analog of vasopressin [10] (3S, 4S)-statin [12] analogs of thyrotropin releasing hormone [13] and the C-peptide of Ribonuclease A [13]. 

These ideas, then, became the strategy for the design for numerous peptoids resembling known renin substrates. The scissile dipeptide was replaced with nonscissile statine and analogous amino acids such as 4-amino-5-cyclohexyl-3-hydoxypentanoic acid (ACHPA) and fluorostatinone to act as presumed transition-state analogs and to become potent renin inhibitors. 

The results described above have several interesting implications. The N-acetyl-statine and N-acetylated statyl dipeptides reversibly bind to the active center of pepsin. The binding of these inhibitors is considerably stronger than their amino acid and peptide analog, as the data in Table I clearly illustrates. While... 

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