Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYTUW29)

• DOT Name: Procathepsin L (CTSL)
• Synonyms: EC 3.4.22.15; Cathepsin L1; Major excreted protein; MEP
• Gene Name: CTSL
• UniProt ID: CATL1_HUMAN
• PDB ID: 1CJL ; 1CS8 ; 1ICF ; 1MHW ; 2NQD ; 2VHS ; 2XU1 ; 2XU3 ; 2XU4 ; 2XU5 ; 2YJ2 ; 2YJ8 ; 2YJ9 ; 2YJB ; 2YJC ; 3BC3 ; 3H89 ; 3H8B ; 3H8C ; 3HHA ; 3HWN ; 3IV2 ; 3K24 ; 3KSE ; 3OF8 ; 3OF9 ; 4AXL ; 4AXM ; 5F02 ; 5I4H ; 5MAE ; 5MAJ ; 5MQY ; 6EZP ; 6EZX ; 6F06 ; 6JD0 ; 6JD8 ; 7QKB ; 7QKC ; 7QKD ; 7W33 ; 7W34 ; 7Z3T ; 7Z58 ; 7ZS7 ; 7ZVF ; 7ZXA ; 8A4U ; 8A4V ; 8A4W ; 8A4X ; 8A5B ; 8AHV ; 8B4F ; 8C77 ; 8GX2 ; 8OFA ; 8OZA ; 8PRX ; 8QKB
• EC Number: 3.4.22.15
• Pfam ID: PF08246 ; PF00112
• Sequence:
  MNPTLILAAFCLGIASATLTFDHSLEAQWTKWKAMHNRLYGMNEEGWRRAVWEKNMKMIE
  LHNQEYREGKHSFTMAMNAFGDMTSEEFRQVMNGFQNRKPRKGKVFQEPLFYEAPRSVDW
  REKGYVTPVKNQGQCGSCWAFSATGALEGQMFRKTGRLISLSEQNLVDCSGPQGNEGCNG
  GLMDYAFQYVQDNGGLDSEESYPYEATEESCKYNPKYSVANDTGFVDIPKQEKALMKAVA
  TVGPISVAIDAGHESFLFYKEGIYFEPDCSSEDMDHGVLVVGYGFESTESDNNKYWLVKN
  SWGEEWGMGGYVKMAKDRRNHCGIASAASYPTV
• Function: Thiol protease important for the overall degradation of proteins in lysosomes (Probable). Plays a critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. Involved in the solubilization of cross-linked TG/thyroglobulin and in the subsequent release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen. In neuroendocrine chromaffin cells secretory vesicles, catalyzes the prohormone proenkephalin processing to the active enkephalin peptide neurotransmitter. In thymus, regulates CD4(+) T cell positive selection by generating the major histocompatibility complex class II (MHCII) bound peptide ligands presented by cortical thymic epithelial cells. Also mediates invariant chain processing in cortical thymic epithelial cells. Major elastin-degrading enzyme at neutral pH. Accumulates as a mature and active enzyme in the extracellular space of antigen presenting cells (APCs) to regulate degradation of the extracellular matrix in the course of inflammation. Secreted form generates endostatin from COL18A1. Critical for cardiac morphology and function. Plays an important role in hair follicle morphogenesis and cycling, as well as epidermal differentiation. Required for maximal stimulation of steroidogenesis by TIMP1; (Microbial infection) In cells lacking TMPRSS2 expression, facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via a slow acid-activated route with the proteolysis of coronavirus spike (S) glycoproteins in lysosome for entry into host cell. Proteolysis within lysosomes is sufficient to activate membrane fusion by coronaviruses SARS-CoV and EMC (HCoV-EMC) S as well as Zaire ebolavirus glycoproteins ; [Isoform 2]: Functions in the regulation of cell cycle progression through proteolytic processing of the CUX1 transcription factor. Translation initiation at downstream start sites allows the synthesis of isoforms that are devoid of a signal peptide and localize to the nucleus where they cleave the CUX1 transcription factor and modify its DNA binding properties.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Apoptosis (hsa04210)
  Antigen processing and presentation (hsa04612)
  Proteoglycans in cancer (hsa05205)
  Rheumatoid arthritis (hsa05323)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Collagen degradation (R-HSA-1442490)
  Degradation of the extracellular matrix (R-HSA-1474228)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  MHC class II antigen presentation (R-HSA-2132295)
  RUNX1 regulates transcription of genes involved in differentiation of keratinocytes (R-HSA-8939242)
  Attachment and Entry (R-HSA-9678110)
  Attachment and Entry (R-HSA-9694614)
  Endosomal/Vacuolar pathway (R-HSA-1236977)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Procathepsin L (CTSL) decreases the response to substance of Cisplatin.	[29]
Paclitaxel	DMLB81S	Approved	Procathepsin L (CTSL) increases the response to substance of Paclitaxel.	[30]
Topotecan	DMP6G8T	Approved	Procathepsin L (CTSL) affects the response to substance of Topotecan.	[31]

24 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Procathepsin L (CTSL).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Procathepsin L (CTSL).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Procathepsin L (CTSL).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Procathepsin L (CTSL).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Procathepsin L (CTSL).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Procathepsin L (CTSL).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Procathepsin L (CTSL).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Procathepsin L (CTSL).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Procathepsin L (CTSL).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Procathepsin L (CTSL).	[10]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Procathepsin L (CTSL).	[11]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Procathepsin L (CTSL).	[2]
Amodiaquine	DME4RA8	Approved	Amodiaquine decreases the activity of Procathepsin L (CTSL).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Procathepsin L (CTSL).	[13]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Procathepsin L (CTSL).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Procathepsin L (CTSL).	[19]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Procathepsin L (CTSL).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Procathepsin L (CTSL).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Procathepsin L (CTSL).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Procathepsin L (CTSL).	[22]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Procathepsin L (CTSL).	[24]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Procathepsin L (CTSL).	[25]
Choline	DM5D9YK	Investigative	Choline affects the expression of Procathepsin L (CTSL).	[26]
1-(1-(thiophen-2-yl)ethylidene)thiosemicarbazide	DMQSEF6	Investigative	1-(1-(thiophen-2-yl)ethylidene)thiosemicarbazide decreases the activity of Procathepsin L (CTSL).	[28]

6 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Berberine	DMC5Q8X	Phase 4	Berberine decreases the cleavage of Procathepsin L (CTSL).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone affects the cleavage of Procathepsin L (CTSL).	[15]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the cleavage of Procathepsin L (CTSL).	[14]
D-glucose	DMMG2TO	Investigative	D-glucose increases the secretion of Procathepsin L (CTSL).	[23]
Bafilomycin A1	DMUNK59	Investigative	Bafilomycin A1 decreases the cleavage of Procathepsin L (CTSL).	[14]
2-APB	DM9AKVR	Investigative	2-APB decreases the cleavage of Procathepsin L (CTSL).	[27]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Procathepsin L (CTSL).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Procathepsin L (CTSL).	[18]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Phenytoin and cyclosporin A suppress the expression of MMP-1, TIMP-1, and cathepsin L, but not cathepsin B in cultured gingival fibroblasts. J Periodontol. 2000 Jun;71(6):955-60. doi: 10.1902/jop.2000.71.6.955.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [9] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [12] The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death. Autophagy. 2013 Dec;9(12):2087-102. doi: 10.4161/auto.26506. Epub 2013 Oct 8.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Berbamine Hydrochloride inhibits lysosomal acidification by activating Nox2 to potentiate chemotherapy-induced apoptosis via the ROS-MAPK pathway in human lung carcinoma cells. Cell Biol Toxicol. 2023 Aug;39(4):1297-1317. doi: 10.1007/s10565-022-09756-8. Epub 2022 Sep 7.
• [15] A role for the autophagy regulator Transcription Factor EB in amiodarone-induced phospholipidosis. Biochem Pharmacol. 2015 Jun 1;95(3):201-9. doi: 10.1016/j.bcp.2015.03.017. Epub 2015 Apr 13.
• [16] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [21] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [23] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.
• [24] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [25] Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. Cancer Res. 2004 Apr 1;64(7):2439-48. doi: 10.1158/0008-5472.can-03-2643.
• [26] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.
• [27] The relationship between Cd-induced autophagy and lysosomal activation in WRL-68 cells. J Appl Toxicol. 2015 Nov;35(11):1398-405. doi: 10.1002/jat.3114. Epub 2015 Jan 29.
• [28] Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms. J Virol. 2013 Jul;87(14):8017-28. doi: 10.1128/JVI.00998-13. Epub 2013 May 15.
• [29] Cathepsin L-mediated resistance of paclitaxel and cisplatin is mediated by distinct regulatory mechanisms. J Exp Clin Cancer Res. 2019 Aug 1;38(1):333. doi: 10.1186/s13046-019-1299-4.
• [30] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.
• [31] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.