Design of Noncovalent Inhibitors of Human Cathepsin L. From the 96-Residue Proregion to Optimized Tripeptides

2002 ◽  
Vol 45 (24) ◽  
pp. 5321-5329 ◽  
Author(s):  
Shafinaz F. Chowdhury ◽  
J. Sivaraman ◽  
Jing Wang ◽  
Gopal Devanathan ◽  
Paule Lachance ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Human Cathepsin

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

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

Mercurial activation of human cathepsin L

1985 ◽  
Vol 13 (6) ◽  
pp. 1157-1157
Author(s):  
ROBERT W. MASON
Keyword(s):  
Cathepsin L ◽  
Human Cathepsin

scholarly journals The identification of the major excreted protein (MEP) from a transformed mouse fibroblast cell line as a catalytically active precursor form of cathepsin L

1987 ◽  
Vol 248 (2) ◽  
pp. 449-454 ◽  
Author(s):  
R W Mason ◽  
S Gal ◽  
M M Gottesman
Keyword(s):  
Sequence Data ◽  
Cathepsin L ◽  
Fibroblast Cell ◽  
Mouse Fibroblast ◽  
Protein Substrates ◽  
3T3 Fibroblasts ◽  
Catalytically Active ◽  
Mouse Fibroblast Cell Line ◽  
Human Cathepsin ◽  
Active Precursor

The major excreted protein (MEP) purified from Kirsten-virus-transformed 3T3 fibroblasts and mature human cathepsin L were compared in respect to a number of catalytic criteria and found to be similar. The Mr of MEP is 39,000, whereas that of mature human cathepsin L is 30,000. Sequence data suggested that MEP could be a pro-form of mouse cathepsin L. Both enzymes acted on the synthetic substrate benzyloxycarbonyl-Phe-Arg-7-(4-methyl)coumarylamide with similar catalytic constants and acted optimally at pH 5.5. Both were rapidly inactivated by the active-site-directed inhibitors benzyloxycarbonyl-Phe-Phe-diazomethane and L-3-carboxy-trans-2,3-epoxypropionyl-leucylamido-(4-guanidin o)butane, and furthermore, 3H-labelled L-3-carboxy-trans-2,3-epoxypropionyl-leucylamido-(4-acetamid o)butane, which binds covalently to the heavy chain of mature cathepsin L, also bound to MEP. MEP autolyses rapidly at pH 3.0 to give lower-Mr (35,000 and 30,000) forms, but all forms react with the radiolabelled inhibitor. No autolysis occurred above pH 5.0. MEP hydrolysed azocasein at pH 5.0, demonstrating that it is capable of hydrolysing protein substrates without autolytic activation. Unlike mature forms of cathepsin L, MEP is stable, but not active, at neutral pH. The present work shows that cathepsin L can be secreted as a higher-Mr precursor that is stable in extracellular fluids but only active where local pH values fall below 6.0. These results suggest that the extra N-terminal peptide on MEP is not an activation peptide, but is a regulatory peptide affecting the pH-stability and activity of mouse cathepsin L.

scholarly journals Acidic pH as a physiological regulator of human cathepsin L activity

2001 ◽  
Vol 259 (3) ◽  
pp. 926-932 ◽  
Author(s):  
Boris Turk ◽  
Iztok Dolenc ◽  
Brigita Lenarčič ◽  
Igor Križaj ◽  
Vito Turk ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Acidic Ph ◽  
Physiological Regulator ◽  
Human Cathepsin

scholarly journals Kinetic Characterization and Molecular Docking of a Novel, Potent, and Selective Slow-Binding Inhibitor of Human Cathepsin L

2008 ◽  
Vol 74 (1) ◽  
pp. 34-41 ◽  
Author(s):  
Parag P. Shah ◽  
Michael C. Myers ◽  
Mary Pat Beavers ◽  
Jeremy E. Purvis ◽  
Huiyan Jing ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cathepsin L ◽  
Kinetic Characterization ◽  
Human Cathepsin ◽  
Slow Binding Inhibitor

scholarly journals Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L

2021 ◽  
Vol 22 (21) ◽  
pp. 11779
Author(s):  
Elisa Costanzi ◽  
Maria Kuzikov ◽  
Francesca Esposito ◽  
Simone Albani ◽  
Nicola Demitri ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Cathepsin L ◽  
Covalent Binding ◽  
Covalent Bond ◽  
Binding Mode ◽  
Space Groups ◽  
Main Protease ◽  
Catalytic Cysteine ◽  
Future Drug ◽  
Human Cathepsin

After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.

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