Protease inhibitors pepsin

Potent inhibitor of add proteases, including pepsin, renin and cathepsin D and many microbial aspartic proteases... 

The intense interest in y - am i n o - (i -hydroxy acid related peptides has led to a great deal of effort devoted to their synthesis. Statine analogues Ahppa (11), Achpa (12), and Dahoa (13) (Scheme 2), which correspond to the replacement of the chain equivalent of leucine in statine by those of phenylalanine, cyclohexylalanine, and lysine, respectively, were used to synthesize inhibitors of pepsin, renin, and penicillinopepsinJ1314] With the objective of developing highly specific inhibitors, C2-substituted analogues have also been introduced into short, substrate-derived inhibitors, e.g. the a,a-difluoro statine 14 in renin inhibitors,1151 and N -substituted statine derivatives like 15 in HIV-1 protease inhibitors.[16]... 

Rich DH, Bernatowicz MS. Synthesis of analogues of the carboxyl protease inhibitor pepstatin. Effect of structure in subsite P3 on inhibition of pepsin. J. Med. Chem. 1982 25 791-795. 

CgH NOj, Mr 175.23, mp. 201-203°C (decomp.), [o] -20 (H2O). An amino acid in pepstatin A, a pentapeptide mixture and inhibitor of the protease pepsin produced by various Streptomyces species. S. and its derivatives are of major importance in the synthesis of pseudopeptidic protease inhibitors as therapeutics for hypertension (as renin inhibitors) and AIDS (as HIV protease inhibitors). 

The first low-molecular weight renin inhibitors were aspartyl protease inhibitors from Actinomycetes, such as pepstatin from Streptomyces testaceus. Pep-statin, originally discovered as apicomolar inhibitor of pepsin, is ahexa-peptide containing the unusual amino acid statine (Sta, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid). [22] Pepstatin is a transition-state inhibitor, suffering the same major drawback as antibodies, namely a lack of oral bioavailabUity. 

Pepstatin is a potent naturally occurring inhibitor of aspartic proteases, including HIV-1 protease and pepsin [29-31]. It will be interesting to investigate the physiological applications of these ferrocene peptide conjugates (see also Section 5.3). 

The alignment of them realized in the tetrapetide allows for a simultaneous inhibition of the proteolytic activity of trypsin-like serine proteases, papain-like cysteine proteases, and pepsin-like aspartyl proteases. Therefore, this unique compound represents a blueprint for the design of protease class-spanning inhibitors [85, 86]. The capability of (59) to inhibit proteases belonging to different classes for trypsin, cathepsin B, cathepsin L, and papain was reported (see Table 30.3). Miraziridine A [85] also inhibited cathepsin B with an IC50 value of 1.4 pg/mL. Aziridine-2,3-dicarboxylic acid (14) is a rare natural product, reported from a Streptomyces [36], and vArg has never before reported as a natural product. 

To study its mode of inhibition, we prepared several derivatives and measured their kinetics of inhibition. Both N-acetyl-statine and N-acetyl-alanyl-statine are competitive inhibitors for pepsin with values of 1.2 X lO M and 5.65 x 10 M, respectively. The value for N-acetyl-valyl-statine is 4.8 x 10 M. These statyl derivatives, therefore, are very strong inhibitors. The value for N-acetyl-statine is 600-fold smaller than that of its structural analog N-acetyl-leucine. The derivative which contains two statyl residues in a tetrapeptide exhibits inhibitory properties which approach those of pepstatin itself. Other acid proteases, human pepsin, human gastricsin, renin, cathepsin D, the acid protease from R. chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. We suggest that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases. 

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