cathepsin S

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2353

Nomenclature: cathepsin S

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	-	331	1q21.3	CTSS	cathepsin S
Mouse	-	340	3 40.74 cM	Ctss	cathepsin S
Rat	-	330	2q34	Ctss	cathepsin S

Previous and Unofficial Names
Cat S

Database Links
Specialist databases
MEROPS	C01.034 (Hs)
Other databases
Alphafold	P25774 (Hs), O70370 (Mm), Q02765 (Rn)
BRENDA	3.4.22.27
ChEMBL Target	CHEMBL2954 (Hs), CHEMBL4098 (Mm), CHEMBL1075217 (Rn)
Ensembl Gene	ENSG00000163131 (Hs), ENSMUSG00000038642 (Mm), ENSRNOG00000021157 (Rn)
Entrez Gene	1520 (Hs), 13040 (Mm), 50654 (Rn)
Human Protein Atlas	ENSG00000163131 (Hs)
KEGG Enzyme	3.4.22.27
KEGG Gene	hsa:1520 (Hs), mmu:13040 (Mm), rno:50654 (Rn)
OMIM	116845 (Hs)
Pharos	P25774 (Hs)
RefSeq Nucleotide	NM_001199739 (Hs), NM_004079 (Hs), NM_001267695 (Mm), NM_017320 (Rn)
RefSeq Protein	NP_004070 (Hs), NP_001186668 (Hs), NP_001254624 (Mm), NP_059016 (Rn)
UniProtKB	P25774 (Hs), O70370 (Mm), Q02765 (Rn)
Wikipedia	CTSS (Hs)

Enzyme Reaction

EC Number: 3.4.22.27

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Inhibitors

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Reference
VBY-825		Mm	Inhibition	10.4	pK_i	1
⤷	pK_i 10.4 (K_i 4x10^-11 M) [1]
VBY-825		Hs	Inhibition	9.9	pK_i	1
⤷	pK_i 9.9 (K_i 1.3x10^-10 M) [1]
compound (R)-26 [PMID: 22686657]		Hs	Inhibition	9.3	pK_i	2
⤷	pK_i 9.3 (K_i 5.5x10^-10 M) [2]
VBY-825		Rn	Inhibition	9.1	pK_i	1
⤷	pK_i 9.1 (K_i 7.7x10^-10 M) [1]
K777		Hs	Inhibition	8.7	pK_i	5
⤷	pK_i 8.7 (K_i 2x10^-9 M) [5]
petesicatib		Hs	Inhibition	10.0	pIC₅₀	7
⤷	pIC₅₀ 10.0 (IC₅₀ 1x10^-10 M) [7]
petesicatib		Mm	Inhibition	9.5	pIC₅₀	7
⤷	pIC₅₀ 9.5 (IC₅₀ 3x10^-10 M) [7]
LHVS		Hs	Inhibition	9.0	pIC₅₀	6
⤷	pIC₅₀ 9.0 (IC₅₀ 1x10^-9 M) [6]
odanacatib		Hs	Inhibition	7.2	pIC₅₀	3
⤷	pIC₅₀ 7.2 (IC₅₀ 6x10^-8 M) [3]

View species-specific inhibitor tables

Immunopharmacology Comments
Cathepsin S is expressed in the lysosome of antigen presenting cells (dendritic cells, B-cells and macrophages) where it processes the invariant chain-MHC-II complex (a chaperone protein that prevents premature peptide loading) inside antigen presenting cells and in this way controls antigen presentation. Due to this role in antigen presentation, inhibition of cathepsin S is expected to cause immunosuppression [8]. This enzyme is also a central pathomechanism in autoimmune diseases. Consequently, cathepsin S inhibitors are being investigated for clinical efficacy in autoimmune conditions. Roche's cathepsin S inhibitor petesicatib (RO5459072 or RG7625) completed Phase 2 clinical evaluation in Sjögren's syndrome (NCT02701985) and Phase 1 in celiac disease (NCT02679014), but there are no active clinical trials registered with ClinicalTrials.gov.

Immunopharmacology Comments

Cathepsin S is expressed in the lysosome of antigen presenting cells (dendritic cells, B-cells and macrophages) where it processes the invariant chain-MHC-II complex (a chaperone protein that prevents premature peptide loading) inside antigen presenting cells and in this way controls antigen presentation. Due to this role in antigen presentation, inhibition of cathepsin S is expected to cause immunosuppression [8]. This enzyme is also a central pathomechanism in autoimmune diseases. Consequently, cathepsin S inhibitors are being investigated for clinical efficacy in autoimmune conditions. Roche's cathepsin S inhibitor petesicatib (RO5459072 or RG7625) completed Phase 2 clinical evaluation in Sjögren's syndrome (NCT02701985) and Phase 1 in celiac disease (NCT02679014), but there are no active clinical trials registered with ClinicalTrials.gov.

Immuno Process Associations

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General Comments
Cathepsin S, is a lysosomal cysteine protease, whch plays an important role in antigen presentation. Selective cathepsin S inhibitors are being developed for their therapeutic potential in autoimmune disorders, atherosclerosis, osteoporosis, osteoarthritis and cancer [4].

References

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1. Elie BT, Gocheva V, Shree T, Dalrymple SA, Holsinger LJ, Joyce JA. (2010) Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model. Biochimie, 92 (11): 1618-24. [PMID:20447439]

2. Frizler M, Schmitz J, Schulz-Fincke AC, Gütschow M. (2012) Selective nitrile inhibitors to modulate the proteolytic synergism of cathepsins S and F. J Med Chem, 55 (12): 5982-6. [PMID:22686657]

3. Gauthier JY, Chauret N, Cromlish W, Desmarais S, Duong le T, Falgueyret JP, Kimmel DB, Lamontagne S, Léger S, LeRiche T et al.. (2008) The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett, 18 (3): 923-8. [PMID:18226527]

4. Lee-Dutra A, Wiener DK, Sun S. (2011) Cathepsin S inhibitors: 2004-2010. Expert Opin Ther Pat, 21 (3): 311-37. [PMID:21342054]

5. Mellott DM, Tseng CT, Drelich A, Fajtová P, Chenna BC, Kostomiris DH, Hsu J, Zhu J, Taylor ZW, Kocurek KI et al.. (2021) A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells. ACS Chem Biol, 16 (4): 642-650. [PMID:33787221]

6. Méthot N, Rubin J, Guay D, Beaulieu C, Ethier D, Reddy TJ, Riendeau D, Percival MD. (2007) Inhibition of the activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing. J Biol Chem, 282 (29): 20836-46. [PMID:17535802]

7. Tato M, Kumar SV, Liu Y, Mulay SR, Moll S, Popper B, Eberhard JN, Thomasova D, Rufer AC, Gruner S et al.. (2017) Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury. Sci Rep, 7 (1): 2775. [PMID:28584258]

8. Thurmond RL, Sun S, Karlsson L, Edwards JP. (2005) Cathepsin S inhibitors as novel immunomodulators. Curr Opin Investig Drugs, 6 (5): 473-82. [PMID:15912960]