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Design and synthesis of inhibitors incorporating ?-amino acids of metalloendopeptidase EC 3.4.24.15

2000; Wiley; Volume: 6; Issue: 9 Linguagem: Inglês

10.1002/1099-1387(200009)6

1099-1387

D.L. Steer, Rebecca A. Lew, Patrick Perlmutter, A. Ian Smith, M.-I. Aguilar,

Enzyme function and inhibition

Journal of Peptide ScienceVolume 6, Issue 9 p. 470-477 Research Article Design and synthesis of inhibitors incorporating β-amino acids of metalloendopeptidase EC 3.4.24.15 D.L. Steer, D.L. Steer Department of Biochemistry & Molecular Biology, Monash University, Victoria 3800, AustraliaSearch for more papers by this authorR.A. Lew, R.A. Lew Baker Medical Research Institute, P.O. Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, AustraliaSearch for more papers by this authorP. Perlmutter, P. Perlmutter Department of Chemistry, Monash University, Victoria 3800, AustraliaSearch for more papers by this authorA.I. Smith, A.I. Smith Baker Medical Research Institute, P.O. Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, AustraliaSearch for more papers by this authorM.-I. Aguilar, Corresponding Author M.-I. Aguilar Department of Biochemistry & Molecular Biology, Monash University, Victoria 3800, AustraliaDepartment of Biochemistry & Molecular Biology, P.O. Box 13D, Monash University, Victoria, 3800, AustraliaSearch for more papers by this author D.L. Steer, D.L. Steer Department of Biochemistry & Molecular Biology, Monash University, Victoria 3800, AustraliaSearch for more papers by this authorR.A. Lew, R.A. Lew Baker Medical Research Institute, P.O. Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, AustraliaSearch for more papers by this authorP. Perlmutter, P. Perlmutter Department of Chemistry, Monash University, Victoria 3800, AustraliaSearch for more papers by this authorA.I. Smith, A.I. Smith Baker Medical Research Institute, P.O. Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, AustraliaSearch for more papers by this authorM.-I. Aguilar, Corresponding Author M.-I. Aguilar Department of Biochemistry & Molecular Biology, Monash University, Victoria 3800, AustraliaDepartment of Biochemistry & Molecular Biology, P.O. Box 13D, Monash University, Victoria, 3800, AustraliaSearch for more papers by this author First published: 15 September 2000 https://doi.org/10.1002/1099-1387(200009)6:9 3.0.CO;2-XCitations: 24AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract Endopeptidase EC 3.4.24.15 (EP 24.15) is a thermolysin-like metalloendopeptidase which is expressed widely throughout the body, with the highest concentrations in the brain, pituitary and testis. While the precise role of EP 24.15 remains unknown, it is thought to participate in the regulated metabolism of a number of specific neuropeptides. Of the limited number of inhibitors described for EP 24.15, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-amino benzoate (CFP) is the most widely studied. CFP is a potent and specific inhibitor, but is unstable in vivo due to its cleavage between the alanine and tyrosine residues by the enzyme neprilysin (EP 24.11). The cpp-Ala-Ala N-terminal product of this cleavage is a potent inhibitor of angiotensin converting enzyme, which further limits the use of CFP in vivo. To generate specific inhibitors of EP 24.15 that are resistant to in vivo proteolysis by EP 24.11, β-amino acids have been incorporated into the structure of CFP. 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