Prolyl endopeptidases

T. C. Friedman, S. Wilk, The Effect of Inhibitors of Prolyl Endopeptidase and Pyro-glutamyl Pephde Hydrolase on TRH Degradation in Rat Serum , Biochem. Biophys. Res. Commun. 1985, 132, 787-794. 

Prolyl endopeptidase (PEP, EC 3.4.21.26) is the only serine protease which is known to cleave a peptide substrate in the C terminal side of a proline residue... 

Metabolism of angiotensinogen by renin produces the decapeptide angiotensin I. This relatively inactive peptide is acted on by a dipeptidase-converting enzyme to produce the very active octapeptide angiotensin II. In addition to converting enzyme, angiotensin I can be acted on by prolyl endopeptidase, an enzyme that removes the first amino acid to form angiotensin 1-7, a peptide primarily active in the brain. ACE has been... 

Some peptides isolated from various fishes and fermented fish have been reported to show prolyl endopeptidase inhibitory activity (Sorensen et al., 2004). The peptides obtained from muscles from salmon, trout, and cod as well as Norwegian fermented trout muscle have been investigated for the potential inhibitory activity for prolyl endopeptidase and found that they are good sources. 

Sorensen, R., Kildal, E., Stepaniak, L., Pripp, A. H., and Sorhaug, T. (2004). Screening for peptides from fish and cheese inhibitory to prolyl endopeptidase. Nahrung/Food 48,53-56. 

In this respect, Scheme 27, the ring opening of /V-sulfonyl p-lactam 80 with a dipeptide affords a-keto amide precursor 81. Subsequent elaboration of 81 and final hydrolysis of the ketal moiety affords poststatin 82, a naturally occurring pentapeptide which shows inhibitory activity against prolyl endopeptidase. 

The title compound, 2-(8-dimethylaminooctylthio)-6-isopropyl-3-pirydyl-2-thienyl ketone (222), a potent competitive reversible inhibitor of the enzyme PEP (prolyl endopeptidase which cleaves a variety of oligopeptides in brain and peripheral tissues217), has been synthesized218 by ["CJalkylation of the iV-desmethyl precursor 223 (equation 117). 222 crosses the BBB and inhibits brain PEP in rodents219. It is used in the study of biodistribution and activity of brain proteases by PET to evaluate the roles... 

Isocyanides, formal divalent carbon functionalities, are ideal candidates for the development of MCRs. Their reaction with carbonyls and imines, through an a-addition process, generates a zwitterionic intermediate, which is then trapped by a nucleophile. The resulting double a-addition adduct is unstable and rapidly undergoes the Mumm rearrangement to afford the final product (Scheme 12.32). The venerable three-component Passerini reaction is the first MCR based on this type of reaction process [116]. It addresses the formation of a-acyloxycarboxamides, which constitute a class of very versatile synthons in organic chemistry. In the present context, this reaction was utilized by Schmidt and collaborators for the elaboration of intermediate 234 [117], a key fragment for the synthesis of the prolyl endopeptidase inhibitor Eurystatin A 231 (Scheme 12.33) [118]. 

Shan, L., Marti, T., Sollid, L.M., Gray, G.M., and Khosla, C. 2004. Comparative biochemical analysis of three bacterial prolyl endopeptidases Implications for coeliac sprue. Biochem J 383(2) 311-318. 

Piper JL, Gray GM, Khosla C. Effect of prolyl endopeptidase on digestive-resistant gliadin peptides in vivo. J Pharmacol Exp Ther 2004 311 213-219. 

Matysiak-Budnik T, Candalh C, Cellier C, Dugave C, Namane A, Vidal-Martinez T, et al. Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease. Gastroenterology 2005 129 786-796. 

Pyle GG, Paaso B, Anderson BE, Allen DD, Marti T, Li Q, et al. Effect of pretreatment of food gluten with prolyl endopeptidase on gluten-induced malabsorption in celiac sprue. Clin Gastroenterol Hepatol 2005 3 687-694. 

Yanai, T, Suzuki, I., Sato, M. (2003). Prolyl endopeptidase inhibitory peptides in wine. Biosc. Biotech. Biochem., 67, 380-382. 

Owens, T. D., Araldi, G. L., Nutt, R. F., Semple, J. E. Concise total synthesis of the prolyl endopeptidase inhibitor eurystatin A via a novel Passerini reaction-deprotection-acyl migration strategy. Tetrahedron Lett. 2001,42, 6271-6274. 

R635 K. Kanai, M. Feher, A. Lopata, B. Podanyi, I. Novik, E. Susan, I. Hermecz and P. Aranyi, Molecular Modeling and CoMFA Studies on Prolyl Endopeptidase Inhibitors , Acta Pharm. Hung., 1999, 69, 240 R636 L. Toke, Supramolecular Chemistry, Crown Ethers , Magy. Kem. Foly., 2000,106, 111... 

FIGURE 41.8 N-acetylation of Z-Gly-ProNH2 protects against the hydrolytic activity of prolyl endopeptidase. ... 

However, sometimes very simple derivatives can afford protection against enzymatic degradation. Thus the V-acetyl derivative of Z-glycyl-prolylamide (Figure 41.8) is six times more resistant to gut prolyl endopeptidase (which normally hydrolyzes the terminal primary amide) than the non-acetylated parent molecule. ... 

M0SS, J., Bundgaard, H. Prodmgs of peptides. 17. Bioreversible deri-vatization of die C-terminal prolineamide residue in peptides to afford protection against prolyl endopeptidase. Int. J. Pharm. 1992, 82, 91—97. 

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