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Article ; Online: Selective inhibition of peripheral cathepsin S reverses tactile allodynia following peripheral nerve injury in mouse.

Eckert, William A / Wiener, John J M / Cai, Hui / Ameriks, Michael K / Zhu, Jian / Ngo, Karen / Nguyen, Steven / Fung-Leung, Wai-Ping / Thurmond, Robin L / Grice, Cheryl / Edwards, James P / Chaplan, Sandra R / Karlsson, Lars / Sun, Siquan

European journal of pharmacology

2020 Volume 880, Page(s) 173171

Abstract: Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells ...

Abstract	Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
MeSH term(s)	Analgesics/pharmacokinetics ; Analgesics/pharmacology ; Analgesics/therapeutic use ; Animals ; Brain/metabolism ; Cathepsins/antagonists & inhibitors ; Cathepsins/genetics ; Cathepsins/metabolism ; Cell Line ; Cytokines/immunology ; Hot Temperature ; Humans ; Hyperalgesia/drug therapy ; Hyperalgesia/immunology ; Immunoglobulin E/immunology ; Immunoglobulin G/immunology ; Immunosuppressive Agents/pharmacokinetics ; Immunosuppressive Agents/pharmacology ; Immunosuppressive Agents/therapeutic use ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Neuralgia/drug therapy ; Neuralgia/immunology ; Peripheral Nerve Injuries/drug therapy ; Peripheral Nerve Injuries/immunology ; Protease Inhibitors/pharmacokinetics ; Protease Inhibitors/pharmacology ; Protease Inhibitors/therapeutic use ; Sciatic Nerve/injuries ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; Tetanus Toxoid/administration & dosage ; Touch
Chemical Substances	Analgesics ; Cytokines ; Immunoglobulin G ; Immunosuppressive Agents ; Protease Inhibitors ; Tetanus Toxoid ; Immunoglobulin E (37341-29-0) ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27)
Language	English
Publishing date	2020-05-11
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2020.173171
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Article ; Online: Women's Imaging.

Thurmond, Amy S

Journal of the American College of Radiology : JACR

2023 Volume 21, Issue 2, Page(s) 222–223

MeSH term(s)	Female ; Humans ; Women's Health ; Diagnostic Imaging
Language	English
Publishing date	2023-10-08
Publishing country	United States
Document type	Letter
ZDB-ID	2274861-1
ISSN	1558-349X ; 1546-1440
ISSN (online)	1558-349X
ISSN	1546-1440
DOI	10.1016/j.jacr.2023.03.025
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Article ; Online: Thioether acetamides as P3 binding elements for tetrahydropyrido-pyrazole cathepsin S inhibitors.

Wiener, Danielle K / Lee-Dutra, Alice / Bembenek, Scott / Nguyen, Steven / Thurmond, Robin L / Sun, Siquan / Karlsson, Lars / Grice, Cheryl A / Jones, Todd K / Edwards, James P

Bioorganic & medicinal chemistry letters

2010 Volume 20, Issue 7, Page(s) 2379–2382

Abstract: A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide ...

Abstract	A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity.
MeSH term(s)	Acetamides/chemistry ; Acetamides/pharmacology ; Cathepsins/antagonists & inhibitors ; Cathepsins/chemistry ; Cathepsins/metabolism ; Cell Line ; Humans ; Models, Molecular ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Structure-Activity Relationship ; Sulfides/chemistry ; Sulfides/pharmacology
Chemical Substances	Acetamides ; Protease Inhibitors ; Pyrazoles ; Sulfides ; pyrazole (3QD5KJZ7ZJ) ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27)
Language	English
Publishing date	2010-04-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2010.01.103
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Article ; Online: Recent advances in the design of cathepsin S inhibitors.

Wiener, John J M / Sun, Siquan / Thurmond, Robin L

Current topics in medicinal chemistry

2010 Volume 10, Issue 7, Page(s) 717–732

Abstract: Cathepsin S has been of increasing interest as a target of medicinal chemistry efforts ... as its involvement in extracellular proteolytic activities. Inhibition of the cathepsin S enzyme reduces degradation ... decreasing antigen presentation to CD4(+) T-cells. Extracellular cathepsin S may also be involved ...

Abstract	Cathepsin S has been of increasing interest as a target of medicinal chemistry efforts given its role in modulating antigen-presentation by major histocompatibility class II (MHC II) molecules as well as its involvement in extracellular proteolytic activities. Inhibition of the cathepsin S enzyme reduces degradation of the invariant chain, a crucial chaperon which also blocks peptide-binding by MHC II molecules, thereby decreasing antigen presentation to CD4(+) T-cells. Extracellular cathepsin S may also be involved in angiogenesis and initiation and/or maintenance of neuropathic pain by cleavage of the membrane-bound chemokine fractalkine (CX3CL1). Cathepsin S inhibitors have thus been suggested to hold potential as therapeutics for a variety of diseases. The initial development of cathepsin S inhibitors targeted irreversible, covalent inhibitors, but more recently the focus has been on reversible inhibitors, representing both covalent modifiers of the enzyme and, of late, noncovalent inhibitors. This review details advances in cathepsin S inhibitor design as reported in the primary literature since 2006, focusing especially on structure-activity relationships of the various covalent and noncovalent inhibitor series.
MeSH term(s)	Animals ; Cathepsins/antagonists & inhibitors ; Cathepsins/chemistry ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/pharmacology ; Drug Design ; Humans ; Structure-Activity Relationship
Chemical Substances	Cysteine Proteinase Inhibitors ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27)
Language	English
Publishing date	2010-03-24
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/156802610791113432
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Article: Pyrazole-based cathepsin S inhibitors with improved cellular potency.

Wei, Jianmei / Pio, Barbara A / Cai, Hui / Meduna, Steven P / Sun, Siquan / Gu, Yin / Jiang, Wen / Thurmond, Robin L / Karlsson, Lars / Edwards, James P

Bioorganic & medicinal chemistry letters

2007 Volume 17, Issue 20, Page(s) 5525–5528

Abstract: High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed ...

Abstract	High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
MeSH term(s)	Animals ; Aza Compounds/chemical synthesis ; Aza Compounds/chemistry ; Aza Compounds/pharmacology ; Benzofurans/chemical synthesis ; Benzofurans/chemistry ; Benzofurans/pharmacology ; Carboxylic Acids/chemical synthesis ; Carboxylic Acids/chemistry ; Carboxylic Acids/pharmacology ; Cathepsins/antagonists & inhibitors ; Cathepsins/metabolism ; Humans ; Indoles/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacology ; Molecular Structure ; Protease Inhibitors/chemical synthesis ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Structure-Activity Relationship ; Thiophenes/chemical synthesis ; Thiophenes/chemistry ; Thiophenes/pharmacology
Chemical Substances	Aza Compounds ; Benzofurans ; Carboxylic Acids ; Indoles ; Protease Inhibitors ; Pyrazoles ; Thiophenes ; pyrazole (3QD5KJZ7ZJ) ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27) ; benzofuran (LK6946W774)
Language	English
Publishing date	2007-10-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2007.08.038
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Article ; Online: Stimulus-induced S-nitrosylation of Syntaxin 4 impacts insulin granule exocytosis.

Wiseman, Dean A / Kalwat, Michael A / Thurmond, Debbie C

The Journal of biological chemistry

2011 Volume 286, Issue 18, Page(s) 16344–16354

Abstract: ... for failure is unclear. Hypothesizing that exocytotic proteins might be targets of S-nitrosylation ... dysfunction, we identified the t-SNARE protein Syntaxin 4 as a target of modification by S-nitrosylation ... The cellular content of S-nitrosylated Syntaxin 4 peaked acutely, within 5 min of glucose stimulation ...

Abstract	Glucose-stimulated insulin release from pancreatic islet β-cells involves increased levels of reactive oxygen and nitrogen species. Although this is normal, under pathophysiological conditions such as chronic hyperglycemia and inflammation, insulin exocytosis fails, and yet the mechanistic reason for failure is unclear. Hypothesizing that exocytotic proteins might be targets of S-nitrosylation, with their dysfunction under conditions of nitrosative stress serving as a mechanistic basis for insulin secretory dysfunction, we identified the t-SNARE protein Syntaxin 4 as a target of modification by S-nitrosylation. The cellular content of S-nitrosylated Syntaxin 4 peaked acutely, within 5 min of glucose stimulation in both human islets and MIN6 β-cells, corresponding to the time at which Syntaxin 4 activation was detectable. S-Nitrosylation was mapped to Syntaxin 4 residue Cys(141), located within the Hc domain predicted to increase accessibility for v-SNARE interaction. A C141S-Syntaxin 4 mutant resisted S-nitrosylation induced in vitro by the nitric oxide donor compound S-nitroso-L-glutathione, failed to exhibit glucose-induced activation and VAMP2 binding, and failed to potentiate insulin release akin to that of wild-type Syntaxin 4. Strikingly, S-nitrosylation of Syntaxin 4 could be induced by acute treatment with inflammatory cytokines (TNFα, IL-1β, and IFNγ), coordinate with inappropriate Syntaxin 4 activation and insulin release in the absence of the glucose stimulus, consistent with nitrosative stress and dysfunctional exocytosis, preceding the cell dysfunction and death associated with more chronic stimulation (24 h). Taken together, these data indicate a significant role for reactive nitrogen species in the insulin exocytosis mechanism in β-cells and expose a potential pathophysiological exploitation of this mechanism to underlie dysfunctional exocytosis.
MeSH term(s)	Animals ; Cell Death/drug effects ; Cell Death/genetics ; Cell Line ; Exocytosis ; Glucose/pharmacology ; Humans ; Insulin/genetics ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Mice ; Protein Processing, Post-Translational ; Protein Structure, Tertiary ; Qa-SNARE Proteins/genetics ; Qa-SNARE Proteins/metabolism ; SNARE Proteins/genetics ; SNARE Proteins/metabolism ; Secretory Vesicles/genetics ; Secretory Vesicles/metabolism ; Secretory Vesicles/pathology ; Sweetening Agents/pharmacology ; Vesicle-Associated Membrane Protein 2/genetics ; Vesicle-Associated Membrane Protein 2/metabolism
Chemical Substances	Insulin ; Qa-SNARE Proteins ; SNARE Proteins ; Sweetening Agents ; VAMP2 protein, human ; Vesicle-Associated Membrane Protein 2 ; vesicle-associated membrane protein 2, mouse ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2011-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.214031
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Article: The SAR of 4-substituted (6,6-bicyclic) piperidine cathepsin S inhibitors.

Grice, Cheryl A / Tays, Kevin / Khatuya, Haripada / Gustin, Darin J / Butler, Christopher R / Wei, Jianmei / Sehon, Clark A / Sun, Siquan / Gu, Yin / Jiang, Wen / Thurmond, Robin L / Karlsson, Lars / Edwards, James P

Bioorganic & medicinal chemistry letters

2006 Volume 16, Issue 8, Page(s) 2209–2212

Abstract: A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier ...

Abstract	A series of competitive, reversible cathepsin S (CatS) inhibitors was investigated. An earlier disclosure detailed the discovery of the 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety as an effective replacement for the 4-arylpiperazin-1-yl group found in our screening hit. Continued investigation into replacements for the 4-aryl piperazine resulted in the identification of potentially useful CatS inhibitors with enzymatic and cellular activity similar to that of JNJ 10329670 as disclosed in a previous publication.
MeSH term(s)	Animals ; Binding Sites ; Bridged Bicyclo Compounds/chemistry ; Bridged Bicyclo Compounds/pharmacology ; Cathepsins/antagonists & inhibitors ; Cell Line, Tumor ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Mice ; Piperidines/chemistry ; Piperidines/pharmacology ; Structure-Activity Relationship
Chemical Substances	Bridged Bicyclo Compounds ; Enzyme Inhibitors ; Piperidines ; piperidine (67I85E138Y) ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27)
Language	English
Publishing date	2006-04-15
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2006.01.038
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Article ; Online: The good and bad effects of cysteine S-nitrosylation and tyrosine nitration upon insulin exocytosis: a balancing act.

Wiseman, Dean A / Thurmond, Debbie C

Current diabetes reviews

2012 Volume 8, Issue 4, Page(s) 303–315

Abstract: As understanding of the mechanisms driving and regulating insulin secretion from pancreatic beta cells grows, there is increasing and compelling evidence that nitric oxide (•NO) and other closely-related reactive nitrogen species (RNS) play important ... ...

Abstract	As understanding of the mechanisms driving and regulating insulin secretion from pancreatic beta cells grows, there is increasing and compelling evidence that nitric oxide (•NO) and other closely-related reactive nitrogen species (RNS) play important roles in this exocytic process. •NO and associated RNS, in particular peroxynitrite, possess the capability to effect signals across both intracellular and extracellular compartments in rapid fashion, affording extraordinary signaling potential. It is well established that nitric oxide signals through activation of guanylate cyclase-mediated production of cyclic GMP. The intricate intracellular redox environment, however, lends credence to the possibility that •NO and peroxynitrite could interact with a wider variety of biological targets, with two leading mechanisms involving 1) Snitrosylation of cysteine, and 2) nitration of tyrosine residues comprised within a variety of proteins. Efforts aimed at delineating the specific roles of •NO and peroxynitrite in regulated insulin secretion indicate that a highly-complex and nuanced system exists, with evidence that •NO and peroxynitrite can contribute in both positive and negative regulatory ways in beta cells. Furthermore, the ultimate biochemical outcome within beta cells, whether to compensate and recover from a given stress, or not, is likely a summation of contributory signals and redox status. Such seeming regulatory dichotomy provides ample opportunity for these mechanisms to serve both physiological and pathophysiologic roles in onset and progression of diabetes. This review focuses attention upon recent accumulating evidence pointing to roles for nitric oxide induced post-translational modifications in the normal regulation as well as the dysfunction of beta cell insulin exocytosis.
MeSH term(s)	Apoptosis ; Cyclic GMP/metabolism ; Cysteine/metabolism ; Cysteine/pharmacology ; Diabetes Mellitus/metabolism ; Exocytosis/drug effects ; Female ; Humans ; Insulin-Secreting Cells/metabolism ; Male ; Nitric Oxide/metabolism ; Oxidation-Reduction ; Peroxynitrous Acid/metabolism ; Peroxynitrous Acid/pharmacology ; Protein Processing, Post-Translational ; Signal Transduction ; Tyrosine/metabolism ; Tyrosine/pharmacology
Chemical Substances	Peroxynitrous Acid (14691-52-2) ; Nitric Oxide (31C4KY9ESH) ; Tyrosine (42HK56048U) ; Cyclic GMP (H2D2X058MU) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2012-05-21
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1875-6417
ISSN (online)	1875-6417
DOI	10.2174/157339912800840514
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Article ; Online: Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1.

Lee-Dutra, Alice / Wiener, Danielle K / Arienti, Kristen L / Liu, Jing / Mani, Neelakandha / Ameriks, Michael K / Axe, Frank U / Gebauer, Damara / Desai, Pragnya J / Nguyen, Steven / Randal, Mike / Thurmond, Robin L / Sun, Siquan / Karlsson, Lars / Edwards, James P / Jones, Todd K / Grice, Cheryl A

Bioorganic & medicinal chemistry letters

2010 Volume 20, Issue 7, Page(s) 2370–2374

Abstract: A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors ...

Abstract	A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
MeSH term(s)	Binding Sites ; Cathepsins/antagonists & inhibitors ; Cathepsins/chemistry ; Cathepsins/metabolism ; Cell Line ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Structure-Activity Relationship ; Sulfides/chemistry ; Sulfides/pharmacology
Chemical Substances	Protease Inhibitors ; Pyrazoles ; Sulfides ; pyrazole (3QD5KJZ7ZJ) ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27)
Language	English
Publishing date	2010-04-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2010.01.108
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Article: Cathepsin S inhibitors as novel immunomodulators.

Thurmond, Robin L / Sun, Siquan / Karlsson, Lars / Edwards, James P

Current opinion in investigational drugs (London, England : 2000)

2005 Volume 6, Issue 5, Page(s) 473–482

Abstract: Cathepsin S is one of the major cysteine proteases, and is expressed in the lysosome ... of antigen presenting cells; primarily dendritic cells, B-cells and macrophages. Cathepsin S is most well known ... via CD1 molecules. Cathepsin S also appears to participate in direct processing of exogenous ...

Abstract	Cathepsin S is one of the major cysteine proteases, and is expressed in the lysosome of antigen presenting cells; primarily dendritic cells, B-cells and macrophages. Cathepsin S is most well known for its critical function in the proteolytic digestion of the invariant chain chaperone molecules, thus controlling antigen presentation to CD4+ T-cells by major histocompatibility complex (MHC) class II molecules or to NK1.1+ T-cells via CD1 molecules. Cathepsin S also appears to participate in direct processing of exogenous antigens for presentation by MHC class II to CD4+ T-cells, or in cross-presentation by MHC class I molecules to CD8+ T-cells. In addition, although direct evidence is still lacking, in its secreted form cathepsin S is implicated in degradation of the extracellular matrix, which may contribute to the pathology of a number of diseases, including arthritis, atherosclerosis and chronic obstructive pulmonary disease. Therefore, inhibition of cathepsin S is a promising target for the development of novel therapeutics for a variety of indications.
MeSH term(s)	Animals ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/immunology ; Cathepsins/antagonists & inhibitors ; Cathepsins/immunology ; Cathepsins/therapeutic use ; Humans ; Immunologic Factors/therapeutic use
Chemical Substances	Immunologic Factors ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27)
Language	English
Publishing date	2005-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2027913-9
ISSN	2040-3429 ; 1472-4472 ; 0967-8298
ISSN (online)	2040-3429
ISSN	1472-4472 ; 0967-8298
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