Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds

ChemMedChem ◽  
2016 ◽  
Vol 11 (10) ◽  
pp. 1042-1047 ◽  
Author(s):  
Maude Giroud ◽  
Michael Harder ◽  
Bernd Kuhn ◽  
Wolfgang Haap ◽  
Nils Trapp ◽  
...  
Keyword(s):  
Cysteine Protease ◽  
Cathepsin L ◽  
Amide Bonds ◽  
Π Stacking ◽  
Phenyl Rings ◽  
Peptide Amide ◽  
Human Cathepsin

Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide⋅⋅⋅Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket

ChemMedChem ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. 257-270 ◽  
Author(s):  
Maude Giroud ◽  
Jakov Ivkovic ◽  
Mara Martignoni ◽  
Marianne Fleuti ◽  
Nils Trapp ◽  
...  
Keyword(s):  
Cysteine Protease ◽  
Cathepsin L ◽  
Stacking Interactions ◽  
Π Stacking ◽  
Human Cathepsin

scholarly journals Cysteine Protease Inhibitor (AcStefin) Is Required for Complete Cyst Formation of Acanthamoeba

2013 ◽  
Vol 12 (4) ◽  
pp. 567-574 ◽  
Author(s):  
Jung-Yub Lee ◽  
Su-Min Song ◽  
Eun-Kyung Moon ◽  
Yu-Ran Lee ◽  
Bijay Kumar Jha ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Cysteine Protease ◽  
Protease Activity ◽  
Cathepsin L ◽  
Cyst Formation ◽  
Cysteine Proteases ◽  
Cysteine Protease Inhibitor ◽  
Content Type ◽  
Human Cathepsin ◽  
Interfering Rna

ABSTRACTThe encystation ofAcanthamoebaleads to the formation of resilient cysts from vegetative trophozoites. This process is essential for parasite survival under unfavorable conditions, such as those associated with starvation, low temperatures, and biocides. Furthermore, cysteine proteases have been implicated in the massive turnover of intracellular components required for encystation. Thus, strict modulation of the activities of cysteine proteases is required to protectAcanthamoebafrom intracellular damage. However, mechanisms underlying the control of protease activity during encystation have not been established inAcanthamoeba. In the present study, we identified and characterizedAcanthamoebacysteine protease inhibitor (AcStefin), which was found to be highly expressed during encystation and to be associated with lysosomes by fluorescence microscopy. Recombinant AcStefin inhibited various cysteine proteases, including human cathepsin B, human cathepsin L, and papain. Transfection with small interfering RNA against AcStefin increased cysteine protease activity during encystation and resulted in incomplete cyst formation, reduced excystation efficiency, and a significant reduction in cytoplasmic area. Taken together, these results indicate that AcStefin is involved in the modulation of cysteine proteases and that it plays an essential role during the encystation ofAcanthamoeba.

Cryptostatin, a chagasin-family cysteine protease inhibitor of Cryptosporidium parvum

Parasitology ◽  
2012 ◽  
Vol 139 (8) ◽  
pp. 1029-1037 ◽  
Author(s):  
J.-M. KANG ◽  
H.-L. JU ◽  
J.-R. YU ◽  
W.-M. SOHN ◽  
B.-K. NA
Keyword(s):  
Cryptosporidium Parvum ◽  
Cysteine Protease ◽  
Cathepsin L ◽  
Sodium Dodecyl ◽  
Cysteine Proteases ◽  
Cysteine Protease Inhibitor ◽  
Immunogold Electron Microscopy ◽  
Electron Microscopy Analysis ◽  
Wide Ph Range ◽  
Human Cathepsin

SUMMARYCysteine proteases of pathogenic protozoan parasites play pivotal roles in the life cycle of parasites, but strict regulation of their activities is also essential for maintenance of parasite physiology and interaction with hosts. In this study, we identified and characterized cryptostatin, a novel inhibitor of cysteine protease (ICP) of Cryptosporidium parvum. Cryptostatin showed low sequence identity to other chagasin-family ICPs, but 3 motifs (NPTTG, GXGG, and RPW/F motifs), which are evolutionarily conserved in chagasin-family ICPs, were found in the sequence. The overall structure of cryptostatin consisted of 8 β-strands that progressed in parallel and closely resembled the immunoglobulin fold. Recombinant cryptostatin inhibited various cysteine proteases, including papain, human cathepsin B, human cathepsin L, and cryptopain-1, with Ki's in the picomolar range. Cryptostatin was active over a wide pH range and was highly stable under physiological conditions. The protein was thermostable and retained its inhibitory activity even after incubation at 95°C. Cryptostatin formed tight complexes with cysteine proteases, so the complexes remained intact in the presence of sodium dodecyl sulfate and β-mercaptoethanol, but they were disassembled by boiling. An immunogold electron microscopy analysis demonstrated diffused localization of cryptostatin within oocystes and meronts, but not within trophozoites, which suggests a possible role for cryptostatin in host cell invasion by C. parvum.

scholarly journals Rational design of human cathepsin L with efficient collagenolytic activity

2020 ◽  
Author(s):  
Debi Choudhury ◽  
Sampa Biswas
Keyword(s):  
Cysteine Protease ◽  
Type I Collagen ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Rational Approach ◽  
Collagenolytic Activity ◽  
Type I ◽  
Cysteine Cathepsins ◽  
Binding Surface ◽  
Human Cathepsin

AbstractCollagens are the main structural components of ECM and collagenolysis is vital for ECM remodelling, which is essential for normal organ homeostasis. Any dysregulation of this process can result in various pathological conditions. The degradation of the interstitial collagens is generally mediated by specific collagenases which are capable of cleaving at specific loci in the collagen triple helix. Lysosomal cysteine cathepsins have general housekeeping as well as some highly specialized functions. Amongst them, human cathepsin K is the only lysosomal cysteine protease which has potent collagenolytic activity against type I collagen. In this study, we have imparted collagenolytic property to another human cysteine protease, cathepsin L, by systematically engineering proline-specificity and GAG-binding surface in the protease. The designed proline-specific mutant shows high specificity for peptidyl substrate containing proline at P2 position but is incapable of cleaving collagen. However, when the proline-specific mutant is further engineered for GAG-binding surface, it can degrade type I collagen in presence of Chondroitin 4-Sulfate (C4-S). We also present high resolution crystal structures of these proline-specific (1.4 Å) and collagen-specific (1.8 Å) mutants. Finally docking studies with prolyl-peptidic substrate (Ala-Gly-Pro-Arg-Ala) at the active site and a GAG molecule (C4-S) at the GAG binding site enables us to identify key structural features responsible for collagenolytic activity of papain-like cysteine proteases. This study provides a rational approach to engineer an efficient collagenase from a human template enzyme which may have various noninvasive therapeutic implications with an expected additional advantage of immuno-compatiblity.

Biphasic modulation of human cathepsin L by a novel cyanobacterial depsipeptide

Planta Medica ◽  
2015 ◽  
Vol 81 (11) ◽  
Author(s):  
B Miller ◽  
M Bertin ◽  
V Hook ◽  
WH Gerwick
Keyword(s):  
Cathepsin L ◽  
Human Cathepsin

A cathepsin L-like cysteine protease is conserved among Babesia equi isolates

2002 ◽  
Vol 119 (2) ◽  
pp. 295-300 ◽  
Author(s):  
Patricia J Holman ◽  
Marlene M Hsieh ◽  
Jessica L Nix ◽  
Kylie G Bendele ◽  
Gerald G Wagner ◽  
...  
Keyword(s):  
Cysteine Protease ◽  
Cathepsin L ◽  
Babesia Equi

scholarly journals Highly potent inhibitors of human cathepsin L identified by screening combinatorial pentapeptide amide collections

2000 ◽  
Vol 267 (16) ◽  
pp. 5085-5092 ◽  
Author(s):  
Achim Brinker ◽  
Ekkehard Weber ◽  
Dieter Stoll ◽  
Jürgen Voigt ◽  
Annett Müller ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Human Cathepsin

Characterization and Crystallization of Recombinant Human Cathepsin L

1996 ◽  
Vol 228 (3) ◽  
pp. 792-796 ◽  
Author(s):  
Toshiyuki Nomura ◽  
Akira Fujishima ◽  
Yukio Fujisawa
Keyword(s):  
Cathepsin L ◽  
Human Cathepsin
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