Design and Synthesis of Dipeptide Nitriles as Reversible and Potent Cathepsin S Inhibitors.

Ward, Yancey D.; Thomson, D. S.; Frye, Leah L.; Cywin, Charles L.; Morwick, Tina M.; Emmanuel, Michel J.; Zindell, Renée; McNeil, Daniel W.; Bekkali, Younes; Girardot, Marc; Hrapchak, Matt; DeTuri, Molly; Crane, Kathleen; White, Della; Pav, Susan; Wang, Yong; Hao, Ming‐Hong; Grygon, Christine A.; Labadia, Mark E.; Freeman, Dorothy M.; Davidson, W.F.; Hopkins, Jerry L.; Brown, Marie; Spero, Denice M.

doi:10.1021/jm030013y

Cited by 6 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As can be seen in Figure 2, the overall fold of procathepsin S is very similar to that of the human cathepsin L‐like subfamily members elucidated so far, procathepsins K and L (PDB 1BY8 and PDB 1CS8, respectively) (Coulombe et al 1996; LaLonde et al 1999; data not shown) to procaricain from Carica papaya (PDB 1PCI) (Groves et al 1996). Regarding the overall structure of the catalytic unit (McGrath et al 1998; Turkenburg et al 2002; Ward et al 2002; Pauly et al 2003), there is no difference between the zymogen and the mature enzyme, just as observed previously for cathepsins L and K when compared to their proenzymes (Coulombe et al 1996; LaLonde et al 1999; Sivaraman et al 1999). Superpositon of mature cathepsin S (PDB 1GLO), (Turkenburg et al 2002) onto the catalytic unit of procathepsin S (this study) results in an RMSD on Cαs of only 0.36 Å with no outliers (largest deviation 1.36 Å).…”

Section: Resultsmentioning

confidence: 51%

The crystal structure of a Cys25 → Ala mutant of human procathepsin S elucidates enzyme–prosequence interactions

et al. 2006

View full text Add to dashboard Cite

The crystal structure of the active-site mutant Cys25 !Ala of glycosylated human procathepsin S is reported. It was determined by molecular replacement and refined to 2.1 Å resolution, with an R-factor of 0.198. The overall structure is very similar to other cathepsin L-like zymogens of the C1A clan. The peptidase unit comprises two globular domains, and a small third domain is formed by the N-terminal part of the prosequence. It is anchored to the prosegment binding loop of the enzyme. Prosegment residues beyond the prodomain dock to the substrate binding cleft in a nonproductive orientation. Structural comparison with published data for mature cathepsin S revealed that procathepsin S residues Phe146, Phe70, and Phe211 adopt different orientations. Being part of the S19 and S2 pockets, they may contribute to the selectivity of ligand binding. Regarding the prosequence, length, orientation and anchoring of helix a3p differ from related zymogens, thereby possibly contributing to the specificity of propeptide-enzyme interaction in the papain family. The discussion focuses on the functional importance of the most conserved residues in the prosequence for structural integrity, inhibition and folding assistance, considering scanning mutagenesis data published for procathepsin S and for its isolated propeptide.

show abstract

Section: Resultsmentioning

confidence: 51%

The crystal structure of a Cys25 → Ala mutant of human procathepsin S elucidates enzyme–prosequence interactions

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Cfor 10 min before initiating the reaction with the addition of 5 mM relevant substrate (Z-Phe-Arg-AMC for Cat L and Cat K, and Z-Val-Val-Arg-AMC for Cat S), respectively 19 . Reactions in microplates were kept at 37 C for another 30 min and then to collect the fluorescent signals from each well in microplates.…”

Section: Cathepsin Activity Assays With Fluorogenic Substratesmentioning

confidence: 99%

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

Tsai

Lee

Chang

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

Elevated cathepsin S (Cat S) level is correlated with higher migration ability in tumor cells. This study investigates the inhibitory effect of novel synthetic a-ketoamide compounds on cathepsin activity and cancer cell migration. The effect of several a-ketoamide compounds on the activity of recombinant cathepsins (Cat S, Cat L and Cat K) was examined. Two highly metastatic cancer cell lines were incubated with three Cat S-specific compounds (6n, 6w and 6r) to analyze their effect on cellular Cat S activity and cell migration. At a 100 nM concentration, compounds 6n, 6r and 6w effectively inhibited Cat S activity. Cat S activity and cell migration were significantly reduced in CL1-3 cells after treatment with either 6n or 6w at 5 mM. Similar results were also obtained when A2058 cells were treated with 6n. These results highlight the therapeutic potential of a-ketoamide compounds, especially 6n and 6w, to prevent or delay cancer metastasis.

show abstract

“…Indeed, such a stabilization of the enzymebound thioimidate becomes evident from a published crystal structure of cathepsin S complexed with a dipeptide nitrile, morpholinocarbonyl-leucyl-O-benzylserine nitrile 37 . The nitrogen atom of the thioimidate group formed from the cyano group by attack of the active-site thiol is in hydrogen bond distances of 3.17 Å and 3.05 Å to the backbone nitrogen of Cys 25 and the side chain nitrogen of Gln 19, respectively ( Figure 6).…”

Section: Inhibitory Activitymentioning

confidence: 99%

Dipeptide-derived nitriles containing additional electrophilic sites: Potentially irreversible inhibitors of cysteine proteases

Löser

Gütschow

2009

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

Design and Synthesis of Dipeptide Nitriles as Reversible and Potent Cathepsin S Inhibitors.

Cited by 6 publications

References 0 publications

The crystal structure of a Cys25 → Ala mutant of human procathepsin S elucidates enzyme–prosequence interactions

The crystal structure of a Cys25 → Ala mutant of human procathepsin S elucidates enzyme–prosequence interactions

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

Dipeptide-derived nitriles containing additional electrophilic sites: Potentially irreversible inhibitors of cysteine proteases

Contact Info

Product

Resources

About