E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors

Radzey H, Rethmeier M, Klimpel D, Grundhuber M, Sommerhoff CP, Schaschke N (2013)
Chemmedchem 8(8): 1314-1321.

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Abstract
Cathepsin C is a papain-like cysteine protease with dipeptidyl aminopeptidase activity that is thought to activate various granule-associated serine proteases. Its exopeptidase activity is structurally explained by the so-called exclusion domain, which blocks the active-site cleft beyond the S2 site and, with its Asp1 residue, provides an anchoring point for the N terminus of peptide and protein substrates. Here, the hydrazide of (2S,3S)-trans-epoxysuccinyl-l-leucylamido-3-methylbutane (E-64c) (k(2)/K-i=140 +/- 5 M-1 s(-1)) is demonstrated to be a lead structure for the development of irreversible cathepsin C inhibitors. The distal amino group of the hydrazide moiety addresses the acidic Asp1 residue at the entrance of the S2 pocket by hydrogen bonding while also occupying the flat hydrophobic S1'-S2' area with its leucine-isoamylamide moiety. Furthermore, structure-activity relationship studies revealed that functionalization of this distal amino group with alkyl residues can be used to occupy the conserved hydrophobic S2 pocket. In particular, the n-butyl derivative was identified as the most potent inhibitor of the series (k(2)/K-i=56000 +/- 1700 M-1 s(-1)).
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Radzey H, Rethmeier M, Klimpel D, Grundhuber M, Sommerhoff CP, Schaschke N. E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem. 2013;8(8):1314-1321.
Radzey, H., Rethmeier, M., Klimpel, D., Grundhuber, M., Sommerhoff, C. P., & Schaschke, N. (2013). E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem, 8(8), 1314-1321. doi:10.1002/cmdc.201300093
Radzey, H., Rethmeier, M., Klimpel, D., Grundhuber, M., Sommerhoff, C. P., and Schaschke, N. (2013). E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem 8, 1314-1321.
Radzey, H., et al., 2013. E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem, 8(8), p 1314-1321.
H. Radzey, et al., “E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors”, Chemmedchem, vol. 8, 2013, pp. 1314-1321.
Radzey, H., Rethmeier, M., Klimpel, D., Grundhuber, M., Sommerhoff, C.P., Schaschke, N.: E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem. 8, 1314-1321 (2013).
Radzey, Hanna, Rethmeier, Markus, Klimpel, Dennis, Grundhuber, Maresa, Sommerhoff, Christian P., and Schaschke, Norbert. “E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors”. Chemmedchem 8.8 (2013): 1314-1321.
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Development of the first internally-quenched fluorescent substrates of human cathepsin C: The application in the enzyme detection in biological samples.
Łęgowska M, Hamon Y, Wojtysiak A, Grzywa R, Sieńczyk M, Burster T, Korkmaz B, Lesner A., Arch Biochem Biophys 612(), 2016
PMID: 27746119

35 References

Data provided by Europe PubMed Central.


Yamamoto, Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1597(), 2002
L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L.
Barrett AJ, Kembhavi AA, Brown MA, Kirschke H, Knight CG, Tamai M, Hanada K., Biochem. J. 201(1), 1982
PMID: 7044372
E-64 analogues as inhibitors of cathepsin B. On the role of the absolute configuration of the epoxysuccinyl group.
Schaschke N, Assfalg-Machleidt I, Machleidt W, Turk D, Moroder L., Bioorg. Med. Chem. 5(9), 1997
PMID: 9354234
Solid-phase synthesis of "mixed" peptidomimetics using Fmoc-protected aza-beta3-amino acids and alpha-amino acids.
Busnel O, Bi L, Dali H, Cheguillaume A, Chevance S, Bondon A, Muller S, Baudy-Floc'h M., J. Org. Chem. 70(26), 2005
PMID: 16355988
Novel azapeptide inhibitors of hepatitis C virus serine protease.
Bailey MD, Halmos T, Goudreau N, Lescop E, Llinas-Brunet M., J. Med. Chem. 47(15), 2004
PMID: 15239657

Morrison, Trends Biochem. Sci. 7(), 1982

Knight, 1986

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