Potent Inhibition of Pepsin and Penicillopepsin by Phosphorus-Containing Peptide Analogues

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Journal of Organic Chemistry




Phosphinic and phosphonic acid peptide derivatives have been evaluated as inhibitors of the aspartic proteases pepsin and penicillopepsin. The most potent of those studied is isovaleryl-Val-Val-LeuP-(O)Phe-Ala-Ala-OMe (4) (Leup represents the phosphonic acid analogue of leucine; (O)Phe represents L-?-phenyllactic acid, the alcohol analogue of phenylalanine), for which the Ki values for pepsin and penicillopepsin are 0.26 and 0.19 nM, respectively. While this compound binds to penicillopepsin with an association rate constant, kon, of (6.5 ± 1.5) x 105 M-1 s-1, it does not show slow- or two-step binding with pepsin. The binding of Cbz-Ala-Ala-LeuP-(O)Phe-OMe (1) to penicillopepsin is strongly dependent on pH: in comparison to pH 4.5, the affinity at pH 3.5 is increased 10-fold and at pH 5.5 it is decreased 40-fold. The two diastereomers of a nonionic phosphinamide analogue (10A, 10B) of a statine-containing inhibitor were prepared; however, both are significantly weaker inhibitors of pepsin than the phosphinic acid itself (7)