TY - JOUR
T1 - Design and evaluation of inhibitors for dipeptidyl peptidase I (Cathepsin C)
AU - Kam, Chih Min
AU - Götz, Marion G.
AU - Koot, Gretchen
AU - McGuire, Michael
AU - Thiele, Dwain L
AU - Hudig, Dorothy
AU - Powers, James C.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants to J.C. Powers (R01GM54401), D. Hudig (R01CA38942), and D.L. Thiele (R01AI24639) and by NIH T32CA09563, which provided support for G.E.K. We thank D. Turk in the Department of Biochemistry and Molecular Biology at the Jozef Stefan Institute in Slovenia for his insights into the crystal structure of DPPI.
PY - 2004/7/15
Y1 - 2004/7/15
N2 - Dipeptidyl peptidase I (DPPI, cathepsin C) is a lysosomal cysteine protease that can activate zymogens of several different serine proteases by one step or sequential removal of dipeptides from the N-termini of the pro-protease protein substrates. To find DPPI inhibitors more suitable for cellular applications than diazomethyl ketones, we synthesized three types of inhibitors: dipeptide acyloxymethyl ketones, fluoromethyl ketones, and vinyl sulfones (VS). The acyloxymethyl ketones inhibited DPPI slowly and are moderate inhibitors of cellular DPPI. The fluoromethyl ketones were potent, but the inhibited DPPI regained activity quickly. The dipeptide vinyl sulfones were effective inhibitors for DPPI, but they also inhibited cathepsins B, H, and L weakly. The best inhibitor, Ala-Hph-VS-Ph, had a k2/KI of 2,000,000M-1s-1. The vinyl sulfones also inhibited intracellular DPPI, and for this application the more stable inhibitors exhibit better potency. We conclude that vinyl sulfones are promising inhibitors to study the intracellular functions of DPPI.
AB - Dipeptidyl peptidase I (DPPI, cathepsin C) is a lysosomal cysteine protease that can activate zymogens of several different serine proteases by one step or sequential removal of dipeptides from the N-termini of the pro-protease protein substrates. To find DPPI inhibitors more suitable for cellular applications than diazomethyl ketones, we synthesized three types of inhibitors: dipeptide acyloxymethyl ketones, fluoromethyl ketones, and vinyl sulfones (VS). The acyloxymethyl ketones inhibited DPPI slowly and are moderate inhibitors of cellular DPPI. The fluoromethyl ketones were potent, but the inhibited DPPI regained activity quickly. The dipeptide vinyl sulfones were effective inhibitors for DPPI, but they also inhibited cathepsins B, H, and L weakly. The best inhibitor, Ala-Hph-VS-Ph, had a k2/KI of 2,000,000M-1s-1. The vinyl sulfones also inhibited intracellular DPPI, and for this application the more stable inhibitors exhibit better potency. We conclude that vinyl sulfones are promising inhibitors to study the intracellular functions of DPPI.
KW - Acyloxymethyl ketones
KW - Cathepsin C
KW - Cysteine protease
KW - Dipeptidyl peptidase I
KW - Dipeptidyl vinyl sulfones
KW - Granzymes
KW - Halomethyl ketones
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U2 - 10.1016/j.abb.2004.04.011
DO - 10.1016/j.abb.2004.04.011
M3 - Article
C2 - 15196986
AN - SCOPUS:2942552395
SN - 0003-9861
VL - 427
SP - 123
EP - 134
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 2
ER -