CTSL

Summary

CTSL (cathepsin L, HGNC:2537) is a protein-coding gene on chromosome 9q21.33, encoding Procathepsin L (P07711). Thiol protease important for the overall degradation of proteins in lysosomes.

The protein encoded by this gene is a lysosomal cysteine proteinase that plays a major role in intracellular protein catabolism. Its substrates include collagen and elastin, as well as alpha-1 protease inhibitor, a major controlling element of neutrophil elastase activity. The encoded protein has been implicated in several pathologic processes, including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria. This protein, which is a member of the peptidase C1 family, is a dimer composed of disulfide-linked heavy and light chains, both produced from a single protein precursor. Additionally, this protein cleaves the S1 subunit of the SARS-CoV-2 spike protein, which is necessary for entry of the virus into the cell.

Source: NCBI Gene 1514 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 62 total
• GTEx eGene: eQTL in 20 tissues, sQTL in 19 (q < 0.05)
• ChEMBL bioactivity: 11 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.93 (unconstrained)
• MANE Select transcript: NM_001912
• Interaction hub: 2,452 STRING partners (top 4% of genes corpus-wide)
• Notable: 62 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2537
Approved symbol	CTSL
Name	cathepsin L
Location	9q21.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ31037
Ensembl gene	ENSG00000135047
Ensembl biotype	protein_coding
OMIM	116880
Entrez	1514

Gene structure

Transcript identifiers

Ensembl transcripts: 71 — 45 protein_coding, 16 retained_intron, 10 nonsense_mediated_decay

MANE Select: ENST00000343150

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 2, TSL 3: 1

ENST00000343150, ENST00000340342, ENST00000342020, ENST00000375894, ENST00000482054, ENST00000495822, ENST00000676466, ENST00000676480, ENST00000676531, ENST00000676576, ENST00000676769, ENST00000676881, ENST00000676909, ENST00000676946, ENST00000676961, ENST00000677019, ENST00000677262, ENST00000677345, ENST00000677349, ENST00000677523, ENST00000677615, ENST00000677638, ENST00000677761, ENST00000677821, ENST00000677864, ENST00000677935, ENST00000677955, ENST00000678259, ENST00000678367, ENST00000678442, ENST00000678596, ENST00000678599, ENST00000678649, ENST00000678654, ENST00000678752, ENST00000678965, ENST00000679025, ENST00000679028, ENST00000679030, ENST00000679141, ENST00000679149, ENST00000679157, ENST00000679252, ENST00000882604, ENST00000882605, ENST00000882606, ENST00000882607, ENST00000882608, ENST00000882609, ENST00000882610, ENST00000882611, ENST00000882612, ENST00000882613, ENST00000882614, ENST00000882615, ENST00000915605, ENST00000915606, ENST00000941021, ENST00000941022, ENST00000941023, ENST00000941024, ENST00000999099, ENST00000999101, ENST00001022872, ENST00001022876, ENST00001022878, ENST00001092742, ENST00001092743, ENST00001092744, ENST00001129899, ENST00001139120

RefSeq mRNA: 10 — MANE Select: NM_001912 NM_001257971, NM_001257972, NM_001257973, NM_001382757, NM_001382758, NM_001382766, NM_001382767, NM_001382768, NM_001912, NM_145918

CCDS: CCDS6675, CCDS94432, CCDS94433

Canonical transcript exons

ENST00000343150 — 8 exons

Exon	Start	End
ENSE00001886667	87726119	87726398
ENSE00003469886	87728027	87728149
ENSE00003495030	87729573	87729735
ENSE00003520790	87727594	87727729
ENSE00003588895	87728585	87728809
ENSE00003636798	87728250	87728396
ENSE00003661419	87730381	87730498
ENSE00004794229	87731008	87731469

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 208.0065 / max 3993.5149, expressed in 1741 samples.

Highest expression (Bgee): stromal cell of endometrium, decidua, placenta, islet of Langerhans, omental fat pad.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CTSL is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 20 tissues and its splicing (sQTL) in 19 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 39 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	eqtl	4.0e-24	-0.23	9:87722756:C:G
Nerve Tibial	eqtl	1.4e-23	-0.24	9:87725948:C:A
Skin Sun Exposed Lower leg	eqtl	1.8e-19	-0.16	9:87725948:C:A
Adipose Subcutaneous	eqtl	1.7e-10	-0.17	9:87727760:C:T
Cells Cultured fibroblasts	eqtl	1.2e-07	-0.14	9:87728865:A:C
Cells Cultured fibroblasts	sqtl	5.9e-07	-1.19	9:87726151:C:T
Colon Transverse	eqtl	6.5e-06	-0.15	9:87723998:A:G
Pancreas	eqtl	1.4e-05	+0.20	9:87684003:G:A
Artery Tibial	eqtl	2.5e-05	-0.16	9:87728865:A:C
Thyroid	sqtl	1.2e-04	+0.95	9:87542681:A:G
Esophagus Muscularis	sqtl	1.6e-04	+1.11	9:87804062:C:T
Lung	eqtl	8.8e-04	-0.12	9:87728865:A:C
Breast Mammary Tissue	eqtl	9.1e-04	-0.10	9:87725948:C:A
Whole Blood	eqtl	1.2e-03	-0.11	9:87740158:G:A
Vagina	sqtl	1.4e-03	+4.02	9:88451489:G:C
Adipose Visceral Omentum	sqtl	1.5e-03	+0.59	9:86974514:A:G
Artery Aorta	eqtl	3.4e-03	-0.15	9:87728865:A:C
Thyroid	eqtl	4.6e-03	+0.15	9:87800305:C:A
Brain Frontal Cortex BA9	eqtl	7.0e-03	+0.61	9:87740922:C:A
Breast Mammary Tissue	sqtl	7.8e-03	+0.80	9:86824061:G:A

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
97232	206.1220	1740
97235	0.7326	284
97234	0.4683	215
205550	0.4647	231
97233	0.2189	98

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.42	gold quality
decidua	UBERON:0002450	98.80	gold quality
placenta	UBERON:0001987	98.78	gold quality
islet of Langerhans	UBERON:0000006	98.66	gold quality
omental fat pad	UBERON:0010414	98.41	gold quality
peritoneum	UBERON:0002358	98.40	gold quality
pericardium	UBERON:0002407	98.24	gold quality
gall bladder	UBERON:0002110	98.19	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.06	gold quality
upper lobe of left lung	UBERON:0008952	98.00	gold quality
endometrium epithelium	UBERON:0004811	97.99	gold quality
left uterine tube	UBERON:0001303	97.98	gold quality
renal medulla	UBERON:0000362	97.96	gold quality
upper lobe of lung	UBERON:0008948	97.94	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.91	gold quality
mucosa of stomach	UBERON:0001199	97.81	gold quality
smooth muscle tissue	UBERON:0001135	97.79	gold quality
right atrium auricular region	UBERON:0006631	97.77	gold quality
right ovary	UBERON:0002118	97.76	gold quality
body of uterus	UBERON:0009853	97.74	gold quality
type B pancreatic cell	CL:0000169	97.73	gold quality
calcaneal tendon	UBERON:0003701	97.70	gold quality
left ovary	UBERON:0002119	97.68	gold quality
layer of synovial tissue	UBERON:0007616	97.65	gold quality
right lung	UBERON:0002167	97.58	gold quality
adult mammalian kidney	UBERON:0000082	97.57	gold quality
left coronary artery	UBERON:0001626	97.56	gold quality
descending thoracic aorta	UBERON:0002345	97.54	gold quality
spleen	UBERON:0002106	97.52	gold quality
thoracic aorta	UBERON:0001515	97.45	gold quality
ascending aorta	UBERON:0001496	97.44	gold quality
left adrenal gland	UBERON:0001234	97.41	gold quality
lymph node	UBERON:0000029	97.39	gold quality
coronary artery	UBERON:0001621	97.38	gold quality
right coronary artery	UBERON:0001625	97.32	gold quality
cardiac atrium	UBERON:0002081	97.29	gold quality
heart left ventricle	UBERON:0002084	97.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.25	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.24	gold quality
ovary	UBERON:0000992	97.23	gold quality
myometrium	UBERON:0001296	97.21	gold quality
aorta	UBERON:0000947	97.20	gold quality
left adrenal gland cortex	UBERON:0035825	97.20	gold quality
cardiac ventricle	UBERON:0002082	97.19	gold quality
lower esophagus	UBERON:0013473	97.19	gold quality
liver	UBERON:0002107	97.18	gold quality
right lobe of liver	UBERON:0001114	97.15	gold quality
heart	UBERON:0000948	97.13	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.12	gold quality
adipose tissue	UBERON:0001013	97.10	gold quality
cartilage tissue	UBERON:0002418	97.10	gold quality
endocervix	UBERON:0000458	97.07	gold quality
apex of heart	UBERON:0002098	97.07	gold quality
right adrenal gland	UBERON:0001233	97.04	gold quality
popliteal artery	UBERON:0002250	97.03	gold quality
tibial artery	UBERON:0007610	97.03	gold quality
right adrenal gland cortex	UBERON:0035827	97.02	gold quality
adrenal cortex	UBERON:0001235	97.00	gold quality
synovial joint	UBERON:0002217	96.99	gold quality
connective tissue	UBERON:0002384	96.99	gold quality
metanephros cortex	UBERON:0010533	96.98	gold quality
vermiform appendix	UBERON:0001154	96.93	gold quality
adrenal gland	UBERON:0002369	96.93	gold quality
right lobe of thyroid gland	UBERON:0001119	96.88	gold quality
right testis	UBERON:0004534	96.80	gold quality
adenohypophysis	UBERON:0002196	96.79	gold quality
left lobe of thyroid gland	UBERON:0001120	96.77	gold quality
vena cava	UBERON:0004087	96.73	gold quality
left testis	UBERON:0004533	96.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.60	gold quality
kidney	UBERON:0002113	96.59	gold quality
pancreas	UBERON:0001264	96.52	gold quality
minor salivary gland	UBERON:0001830	96.49	gold quality
parietal pleura	UBERON:0002400	96.49	gold quality
tendon of biceps brachii	UBERON:0008188	96.49	gold quality
thyroid gland	UBERON:0002046	96.48	gold quality
tibial nerve	UBERON:0001323	96.38	gold quality
tendon	UBERON:0000043	96.33	gold quality
pleura	UBERON:0000977	96.29	gold quality
pituitary gland	UBERON:0000007	96.28	gold quality
rectum	UBERON:0001052	96.25	gold quality
caecum	UBERON:0001153	96.24	gold quality
lower lobe of lung	UBERON:0008949	96.23	gold quality
lung	UBERON:0002048	96.19	gold quality
transverse colon	UBERON:0001157	96.13	gold quality
saliva-secreting gland	UBERON:0001044	96.10	gold quality
amniotic fluid	UBERON:0000173	96.09	gold quality
body of pancreas	UBERON:0001150	95.97	gold quality
cortex of kidney	UBERON:0001225	95.97	gold quality
pigmented layer of retina	UBERON:0001782	95.90	gold quality
visceral pleura	UBERON:0002401	95.75	gold quality
right uterine tube	UBERON:0001302	95.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.68	gold quality
testis	UBERON:0000473	95.63	gold quality
colonic epithelium	UBERON:0000397	95.62	gold quality
urethra	UBERON:0000057	95.59	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.54	gold quality
spinal cord	UBERON:0002240	95.44	gold quality
superficial temporal artery	UBERON:0001614	95.41	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	5080.62
E-MTAB-10287	yes	4228.65
E-MTAB-8142	yes	2917.39
E-MTAB-7407	yes	2661.46
E-GEOD-84465	yes	2112.02
E-MTAB-9801	yes	1676.84
E-HCAD-1	yes	89.80
E-CURD-122	yes	72.09
E-MTAB-6678	yes	41.41
E-MTAB-10042	yes	28.32
E-HCAD-9	yes	23.19
E-CURD-112	yes	19.73
E-GEOD-130148	yes	19.52
E-MTAB-9467	yes	18.32
E-MTAB-9067	yes	7.93

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Placenta	tissue	529.1	high
Liver	tissue	311.6	medium
Adipose tissue	tissue	207.7	not detected
Urinary bladder	tissue	195.4	low
Kidney	tissue	193.3	high
Parathyroid gland	tissue	141.8
Appendix	tissue	128.4	high
Ovary	tissue	122.0	medium
Smooth muscle	tissue	116.9	low
Lung	tissue	115.3	medium
Endometrium 1	tissue	101.3	medium
Heart muscle	tissue	99.5	high
Lymph node	tissue	94.6	low
Spleen	tissue	89.4	low
Seminal vesicle	tissue	86.3	low
Bone marrow	tissue	80.0	low
Gallbladder	tissue	79.7	medium
Epididymis	tissue	77.0	high
Testis	tissue	74.9	high
Tongue	tissue	74.6
Thyroid gland	tissue	71.3	medium
Salivary gland	tissue	68.0	medium
Adrenal gland	tissue	68.0	high
Fallopian tube	tissue	67.9	high
Prostate	tissue	63.9	medium
Cervix	tissue	60.2	medium
Choroid plexus	tissue	59.3
Pituitary gland	tissue	58.8
Rectum	tissue	55.2	high
Pancreas	tissue	54.3	medium
Colon	tissue	53.9	high
Skeletal muscle	tissue	53.0	medium
Tonsil	tissue	46.2	medium
Vagina	tissue	45.2	not detected
Breast	tissue	44.1	medium
Duodenum	tissue	37.4	high
Esophagus	tissue	31.1	not detected
Thymus	tissue	30.8
Retina	tissue	29.9
Stomach 1	tissue	29.2	medium
Small intestine	tissue	26.8	medium
Locus coeruleus	tissue	24.4
Nucleus accumbens	tissue	18.5
Postcentral gyrus	tissue	15.5
Hippocampus	tissue	14.3	low
Skin 1	tissue	13.9	not detected
Olfactory bulb	tissue	9.8
Corpus callosum	tissue	9.2
Cerebellum	tissue	8.8	not detected
Cerebral cortex	tissue	8.3	low
Hippocampal formation	tissue	8.3
Entorhinal cortex	tissue	8.3
Temporal cortex	tissue	8.3
Insular cortex	tissue	8.0
Amygdala	tissue	7.9
Retrosplenial cortex	tissue	7.6
Basal ganglia	tissue	7.4	low
Cingulate cortex	tissue	7.4
Prefrontal cortex	tissue	7.3
Ventral pallidum	tissue	7.3

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Anterior thalamic nucleus, ventral (162.8), Blood vessel (102.9), Lateral funiculus (white matter) (41.9), Corpus callosum, splenium (white matter) (38.1), Dorsolateral tegmental area (37.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPG, EGR1, FOS, FOXO1, FOXO3, GLI2, JUN, PPARA, PPARG, SP1, SP2, SP3, STAT1, TP53

miRNA regulators (miRDB)

Targeting CTSL by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

25 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4463	98.56	66.05	1071
HSA-MIR-6072	98.00	66.47	804
HSA-MIR-12127	97.93	66.67	793
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-3529-5P	97.12	67.06	440
HSA-MIR-6891-3P	95.80	65.76	683
HSA-MIR-548AD-3P	94.39	66.04	350
HSA-MIR-3713	94.12	60.05	70

Functional genomics

gnomAD constraint: pLI 1.02e-05, LOEUF 0.932, missense Z 1.2 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000343150 — one region, missense o/e 0.89.

Literature-anchored findings (GeneRIF, showing 40)

• cis-acting element on cathepsin L mRNA can be bound by a negative trans-acting regulator, thus leading to reduced expression rates (PMID:11767948)
• its activity resulted in extensive bone destruction in both cholesteatomas and noncholesteatomas of the middle ear (PMID:11771045)
• Characterization and comparative mapping of the porcine CTSL gene indicates a novel synteny between HSA9q21–>q22 and SSC10q11–>q12 (PMID:11978977)
• the subcellular distribution of cathepsin B, L, and S ativities underwent a shift from endosome to lysosome localization during monocyte differentiation in cell culture (PMID:12437117)
• suppression of cathepsin L expression in A549 cells leads to a growth inhibition which is partially compensated by an upregulation of IL-8 production. (PMID:12437119)
• cathepsin K and L processed high-molecular weight kininogen under stoichiometric conditions, only cathepsin L generated significant amounts of immunoreactive kinins. Cathepsin L exhibited higher specificity constants (kcat/Km) than tissue kallikrein (PMID:12492488)
• lack of involvement in degrading MHC class II-associated invariant chain in nonprofessional antigen-presenting cells (PMID:12748383)
• These results show that cathepsin L is secreted from human fibroblasts in response to external stimuli and plays an important role in IL-8 processing in inflammatory sites. (PMID:12818188)
• The expression of cathepsin L in non-small cell lung cancer is not related to the patients’ outcome at a statistically significant level. (PMID:12926111)
• insulin-stimulated cathepsin L expression in skeletal muscle is impaired in diabetic but not in nondiabetic monozygotic twins, suggesting that the changes may be secondary to impaired glucose metabolism. (PMID:12941783)
• Cathepsin L is released and catalytically active in T lymphocyte cytosol during supraoptimal activation-induced apoptosis of T cells in vitro and may participate in high dose tolerance in vivo. (PMID:15100281)
• endothelial cell-associated cathepsins B and L are not involved in the invasive growth of capillaries from existing blood vessels and the presence of collagen is necessary for MMP2 expression in endothelial cells (PMID:15255544)
• The function of cathepsin L (catL) in the proteolytic network of human lung epithelial cells and its role in the regulation of apoptosis. (PMID:15318816)
• serum level of cathepsin L can serve as a marker of bone resorption and bone density (PMID:15454886)
• Peptide fragment of p47 SEP is a reversible competitive inhibitor of cathepsin L. (PMID:15498563)
• Mechanical stress (compression and tension forces) causes an increase in secretion of cathepsins B and L in periodontal ligament cells in vitro. (PMID:15512772)
• Data suggest that cathepsin L has a critical role in the integration of circulating endothelial progenitor cells (EPC) into ischemic tissue and is required for EPC-mediated neovascularization. (PMID:15665831)
• cathepsins B and L have roles in atypical pituitary adenoma (PMID:15816632)
• cathepsin and inhibitor expression was not different between central and peripheral meningioma tissue or between histological subtypes of meningiomas with the exception of cathepsin L, the level of which was significantly lower in transitional meningiomas (PMID:15832773)
• cathepsin L is over-expressed in human AAA and atherosclerotic lesions and its expression in vascular cell types found in these lesions is regulated by pro-inflammatory cytokines. (PMID:15982660)
• The presence of active cathepsins L, K and S suggests that they contribute to the extracellular breakdown of the extracellular matrix. (PMID:16354158)
• highest expression of Cat L was found in psoriasis, atopic eczema and squamous cell carcinoma (PMID:16433682)
• Identification of CTSV & CTSL as targets for cystatin M/E, their (co)-expression in the stratum granulosum of skin, and activity of CTSL toward transglutaminase 3 strongly imply an important role for them in the differentiation process of human epidermis. (PMID:16565075)
• Results showed that the breast cancer cell line exhibiting the highest in vitro invasiveness also expressed the highest amount of cathepsin L splice variant L-A3. (PMID:16740135)
• CTSL is expressed in the brain of these compound mutants, predominantly in neurons of the cerebral cortex and in Purkinje cells of the cerebellum, where it appears to prevent neuronal cell death (PMID:16913838)
• the 32-kDa cathepsin L found in HT 1080 cell medium is involved in cancer invasion and metastasis (PMID:16918298)
• analysis of human cathepsins K, L, and S iunteractions with elastins (PMID:17227755)
• level of active cathepsin B and L is increased in tumors (PMID:17519890)
• Results describe the structure of chagasin in complex with the host cysteine protease, cathepsin L, at 1.75 A resolution. (PMID:17561110)
• over-expression of VEGF in human glioblastoma cells induces cathepsin L expression at the transcriptional level. This mechanism could be involved in the enhanced tumorogenic potential of these cells. (PMID:17574778)
• Results describe the participation of cathepsin L in adipogenesis and glucose intolerance. (PMID:17643114)
• Here we demonstrate a role for cathepsin L (CatL) cleavage of Ebola virus GP in the generation of a stable 18-kDa GP1 viral intermediate that exhibits increased binding to and infectivity for susceptible cell targets. (PMID:17928356)
• did not detect any plasminogen degradation by cathepsins B, K and L. (PMID:18163891)
• shortening the heavy-light chain loop does not change substrate affinity but does influence activity, in part via conformational change (PMID:18221013)
• These results indicated that in vivo a tumour hypoxic environment up-regulates cathepsin L expression which promotes tumour progression. (PMID:18366346)
• Cathepsin L has a role in processing and activation of proheparanase through multiple cleavages of a linker segment (PMID:18450756)
• cathepsin L is involved in death of macrophages, necrotic core formation and development of atherosclerotic plaque instability (PMID:18495127)
• blood levels are significantly elevated in patients with colorectal adenoma and colorectal carcinoma (PMID:18616803)
• Cathepsin L is required for invasion of endothelial progenitor cells (EPC) into ischemic tissue; thereby its reduction may limit the functional capacity of EPC to improve neovascularization in diabetics. (PMID:18619973)
• Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis. (PMID:18658137)

Cross-species orthologs

35 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctsl.1	ENSDARG00000003902
danio_rerio	zgc:103438	ENSDARG00000035663
danio_rerio	si:dkey-267n13.1	ENSDARG00000035665
danio_rerio	ctss1	ENSDARG00000036940
danio_rerio	tinagl1	ENSDARG00000061231
danio_rerio	ctsf	ENSDARG00000063095
danio_rerio	zgc:110239	ENSDARG00000077664
danio_rerio	si:zfos-1897c11.1	ENSDARG00000077910
danio_rerio	si:dkey-183k8.2	ENSDARG00000089026
danio_rerio	si:dkey-228a15.1	ENSDARG00000095698
danio_rerio	zgc:123103	ENSDARG00000099200
danio_rerio	ctsbb	ENSDARG00000101051
drosophila_melanogaster	CtsB	FBGN0030521
drosophila_melanogaster	CtsL4	FBGN0032228
drosophila_melanogaster	CtsL2	FBGN0033874
drosophila_melanogaster	Swim	FBGN0034709
drosophila_melanogaster	CtsL3	FBGN0037396
drosophila_melanogaster	CtsK1	FBGN0250848
drosophila_melanogaster	CtsF	FBGN0260462
caenorhabditis_elegans		WBGENE00000781
caenorhabditis_elegans		WBGENE00000782
caenorhabditis_elegans		WBGENE00000784
caenorhabditis_elegans		WBGENE00000785
caenorhabditis_elegans	cpz-1	WBGENE00000788
caenorhabditis_elegans		WBGENE00007055
caenorhabditis_elegans	F26E4.3	WBGENE00009158
caenorhabditis_elegans		WBGENE00013072
caenorhabditis_elegans		WBGENE00013076
caenorhabditis_elegans		WBGENE00013764
caenorhabditis_elegans		WBGENE00016300
caenorhabditis_elegans		WBGENE00016306
caenorhabditis_elegans		WBGENE00019314
caenorhabditis_elegans		WBGENE00019986
caenorhabditis_elegans		WBGENE00022189
caenorhabditis_elegans		WBGENE00044760

Paralogs (12): CTSZ (ENSG00000101160), CTSH (ENSG00000103811), CTSC (ENSG00000109861), CTSV (ENSG00000136943), TINAG (ENSG00000137251), TINAGL1 (ENSG00000142910), CTSK (ENSG00000143387), CTSS (ENSG00000163131), CTSB (ENSG00000164733), CTSW (ENSG00000172543), CTSF (ENSG00000174080), CTSO (ENSG00000256043)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88564) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 115 distinct phenotype terms.

Mouse phenotype (MP)	Records
alopecia	7
epidermal hyperplasia	5
decreased CD4-positive, alpha-beta T cell number	5
thick epidermis	4
postnatal lethality, incomplete penetrance	4
abnormal coat/ hair morphology	3
dermatitis	3
acanthosis	3
abnormal hair growth	3
abnormal hair shaft morphology	3
abnormal hair follicle morphology	2
sparse hair	2
delayed hair appearance	2
abnormal hair cycle	2
enlarged sebaceous gland	2
enlarged lymph nodes	2
skin lesions	2
thick dermal layer	2
absent vibrissae	2
excessive scratching	2
abnormal immune system organ morphology	2
abnormal hair follicle development	2
increased CD8-positive, alpha-beta T cell number	2
increased keratinocyte proliferation	2
orthokeratosis	2

+90 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	P61276	100.0%	Diamond
Macaca mulatta	P61277	100.0%	Diamond
Ananas macrodontes	P83447	100.0%	Diamond
Oryza sativa Indica Group	A2XQE8	99.7%	Diamond
Leishmania mexicana	P25775	99.7%	Diamond
Bos taurus	P25975	99.7%	Diamond
Leishmania pifanoi	P35591	99.7%	Diamond
Oryza sativa Japonica Group	Q7XWK5	99.7%	Diamond
Actinidia deliciosa	A5HII1	98.4%	Diamond
Actinidia chinensis var. chinensis	P00785	98.4%	Diamond
Hordeum vulgare	P25249	98.1%	Diamond
Vanilla planifolia	A0A0F7G352	98.0%	Diamond
Canis lupus familiaris	Q3ZKN1	96.4%	Diamond
Sus scrofa	Q9GLE3	96.4%	Diamond
Chlorocebus aethiops	Q9GKL8	96.1%	Diamond
Oryctolagus cuniculus	P43236	95.8%	Diamond
Rattus norvegicus	O35186	95.4%	Diamond
Mus musculus	P55097	95.4%	Diamond
Ovis aries	P83205	94.6%	Diamond
Salvelinus alpinus	Q70SU7	94.4%	Diamond
Paramecium tetraurelia	A0E358	94.3%	Diamond
Saimiri boliviensis boliviensis	Q8HY82	94.0%	Diamond
Plasmodium falciparum 3D7	Q8I6U4	93.4%	Diamond
Vigna mungo	P12412	93.1%	Diamond
Phaseolus vulgaris	P25803	93.1%	Diamond
Vasconcellea cundinamarcensis	P32956	93.0%	Diamond
Tabernaemontana divaricata	A5YVK8	91.3%	Diamond
Carica papaya	P05993	90.0%	Diamond
Zea mays	Q10717	88.8%	Diamond
Arabidopsis thaliana	Q9SUS9	88.4%	Diamond
Brassica napus	P25251	87.7%	Diamond
Ananas comosus	O23791	86.2%	Diamond
Dermatophagoides pteronyssinus	P08176	84.4%	Diamond
Ricinus communis	O65039	82.8%	Diamond
Jacaratia mexicana	P84346	81.9%	Diamond
Entamoeba histolytica HM-1:IMSS	Q01957	80.6%	Diamond
Gallus gallus	P09648	79.8%	Diamond
Sarcophaga peregrina	Q26636	79.2%	Diamond
Zingiber officinale	P82473	78.9%	Diamond
Philibertia gilliesii	P84789	77.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
DAPK1	protein-coding	1612
DAPK1-IT1	ncRNA	100506897

Protein

Protein identifiers

Procathepsin L — P07711 (reviewed: P07711)

Alternative names: Cathepsin L1, Major excreted protein

All UniProt accessions (9): A0A7I2V2H7, A0A7I2V484, A0A7I2V5F7, A0A7I2V5M3, A0A7I2V601, A0A7I2YQA2, A0A7I2YQB5, P07711, Q5T8F0

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease important for the overall degradation of proteins in lysosomes. 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. 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.

Subunit / interactions. Dimer of a heavy and a light chain linked by disulfide bonds. Interacts with Long isoform of CD74/Ii chain; the interaction stabilizes the conformation of mature CTSL.

Subcellular location. Lysosome. Apical cell membrane. Cytoplasmic vesicle. Secretory vesicle. Chromaffin granule. Secreted. Extracellular space. Secreted Nucleus.

Post-translational modifications. During export along the endocytic pathway, pro-CTSL undergoes several proteolytic cleavages to generate the CTSL single-chain and two-chain mature forms, composed of a heavy chain linked to a light chain by disulfide bonds. Autocleavage; produces the single-chain CTSL after cleavage of the propeptide. The cleavage can be intermolecular.

Activity regulation. Inhibited by the propeptide produced by autocleavage. Long isoform of CD74/Ii chain stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of APCs. IFNG enhances the conversion into the CTSL mature and active form. Inhibited by CST6. Inhibited by the glycopeptide antibiotic teicoplanin. Inhibited by amantadine.

Similarity. Belongs to the peptidase C1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P07711-1	1	yes
P07711-3	2

RefSeq proteins (10): NP_001244900, NP_001244901, NP_001244902, NP_001369686, NP_001369687, NP_001369695, NP_001369696, NP_001369697, NP_001903, NP_666023 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000169	Pept_cys_AS	Active_site
IPR000668	Peptidase_C1A_C	Domain
IPR013128	Peptidase_C1A	Family
IPR013201	Prot_inhib_I29	Domain
IPR025660	Pept_his_AS	Active_site
IPR025661	Pept_asp_AS	Active_site
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR039417	Peptidase_C1A_papain-like	Domain

Pfam: PF00112, PF08246

Enzyme classification (BRENDA)

• EC 3.4.22.15 — cathepsin L (BRENDA: 65 organisms, 391 substrates, 936 inhibitors, 123 Km, 114 kcat entries)
• EC 3.4.22.43 — cathepsin V (BRENDA: 2 organisms, 70 substrates, 61 inhibitors, 19 Km, 19 kcat entries)
• EC 3.4.22.B49 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

100 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-PHE-ARG-4-METHYLCOUMARIN 7-AMI	0.0007–0.0342	13
BENZYLOXYCARBONYL-PHE-ARG-7-AMIDO-4-METHYLCOUMAR	0.0011–0.0157	9
BENZYLOXYCARBONYL-PHE-ARG-7-AMIDO-4-METHYLCOUMAR	0.0044–0.0069	7
L-PHE-L-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0003–0.0005	6
BENZYLOXYCARBONYL-L-PHE-L-ARG-7-AMIDO-4-METHYLCO	0.0057–0.0488	4
BENZYLOXYCARBONYL-GLY-PRO-ARG-7-AMIDO-4-METHYLCO	0.014–0.081	2
BENZYLOXYCARBONYL-LEU-ARG-7-AMIDO-4-METHYLCOUMAR	0.0013–0.0098	2
EFL-4-NITROANILIDE	0.2632–1.026	2
L-VAL-L-LEU-L-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0069–0.0124	2
VLK-4-NITROANILIDE	0.0061–0.0664	2
Z-PHE-ARG-4-METHYL-7-COUMARYL AMIDE	0.0041–0.0048	2
2-AMINOBENZOYL-ALA-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0004	1
2-AMINOBENZOYL-ARG-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0002	1
2-AMINOBENZOYL-ASN-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0007	1
2-AMINOBENZOYL-GLN-LEU-ARG-SER-SER-LYS-GLN-N-(2,	0.0008	1

UniProt features (69 total): strand 17, helix 14, binding site 11, turn 6, site 4, chain 3, disulfide bond 3, active site 3, propeptide 2, sequence conflict 2, signal peptide 1, glycosylation site 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

showing 30 of 64 structures by resolution:

PDB	Title	Method	Resolution (Å)
2XU3	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	0.9
5MAE	CATHEPSIN L IN COMPLEX WITH …	X-RAY DIFFRACTION	1
5MAJ	CATHEPSIN L IN COMPLEX WITH …	X-RAY DIFFRACTION	1
2XU4	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.12
5MQY	CATHEPSIN L IN COMPLEX WITH …	X-RAY DIFFRACTION	1.13
2YJC	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.14
2YJ2	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.15
3HHA	Crystal structure of cathepsin L in complex with AZ12878478	X-RAY DIFFRACTION	1.27
2YJ8	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.3
2YJ9	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.35
7Z58	Crystal structure of human Cathepsin L in complex with covalently bound Calpeptin	X-RAY DIFFRACTION	1.35
6EZP	CATHEPSIN L IN COMPLEX WITH …	X-RAY DIFFRACTION	1.37
2YJB	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.4
8A4W	Crystal structure of human cathepsin L with covalently bound Cathepsin L inhibitor IV	X-RAY DIFFRACTION	1.4
8UAC	CATHEPSIN L IN COMPLEX WITH AC1115	X-RAY DIFFRACTION	1.4
5I4H	Caught in the Act: The Crystal Structure of cleaved Cathepsin L bound to the active site …	X-RAY DIFFRACTION	1.42
5F02	CATHEPSIN L IN COMPLEX WITH …	X-RAY DIFFRACTION	1.43
2XU1	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.45
6JD8	Structure of a proline specific mutant of human cathepsin L	X-RAY DIFFRACTION	1.46
2VHS	Cathsilicatein, a chimera	X-RAY DIFFRACTION	1.5
7QKD	Crystal structure of human Cathepsin L in complex with covalently bound MG132	X-RAY DIFFRACTION	1.5
2XU5	CATHEPSIN L WITH A NITRILE INHIBITOR	X-RAY DIFFRACTION	1.6
7Z3T	Crystal structure of apo human Cathepsin L	X-RAY DIFFRACTION	1.6
7ZS7	Crystal structure of human cathepsin L with covalently bound calpain inhibitor VI	X-RAY DIFFRACTION	1.6
7ZVF	Crystal structure of human cathepsin L in complex with covalently bound CLIK148	X-RAY DIFFRACTION	1.6
7ZXA	Crystal structure of human cathepsin L with covalently bound aloxistatin (E-64D)	X-RAY DIFFRACTION	1.6
8QKB	Crystal structure of human cathepsin L in complex with the vinyl sulfone inhibitor K777	X-RAY DIFFRACTION	1.6
8A4V	Crystal structure of human cathepsin L with covalently bound E-64	X-RAY DIFFRACTION	1.65
7QKC	Crystal structure of human Cathepsin L after incubation with Sulfo-Calpeptin	X-RAY DIFFRACTION	1.69
8AHV	Crystal structure of human cathepsin L in complex with calpain inhibitor XII	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07711-F1	93.75	0.88

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; vesicles

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (7)

Position	Role
106–107	cleavage; by autolysis
107–108	cleavage; by autolysis
112–113	cleavage; by autolysis
113–114	cleavage; by autolysis
138
276
300

Ligand- & substrate-binding residues (11)

Position	Role
163	Zn(2+)
184	Zn(2+)
199	Zn(2+)
205	Zn(2+)
209	Zn(2+)
227	Zn(2+)
250	Zn(2+)
253	Zn(2+)
273	Zn(2+)
275	Zn(2+)
122	Zn(2+)

Disulfide bonds (3)

Type	Positions
Disulfide bond	135–178, 169–211
Interchain (between heavy and light chains)	269–322

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	221

Mutagenesis-validated functional residues (1)

Position	Phenotype
138	catalytically inactive. unable to autocleave procathepsin l.

Function

Pathways and Gene Ontology

Reactome pathways

12 curated (TAS) of 44; 9 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

44 pathways:

ID	Pathway	Evidence
R-HSA-9678110	Attachment and Entry ⚕	curated
R-HSA-9694614	Attachment and Entry ⚕	curated
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures	curated
R-HSA-1442490	Collagen degradation	curated
R-HSA-9766229	Degradation of CDH1	curated
R-HSA-1474228	Degradation of the extracellular matrix	curated
R-HSA-2024096	HS-GAG degradation	curated
R-HSA-2132295	MHC class II antigen presentation	curated
R-HSA-9979719	Processing of antigen in germinal center B cells	curated
R-HSA-8939242	RUNX1 regulates transcription of genes involved in differentiation of keratinocytes	curated
R-HSA-9958810	SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	curated
R-HSA-1679131	Trafficking and processing of endosomal TLR	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-9772572	Early SARS-CoV-2 Infection Events ⚕	—
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9679506	SARS-CoV Infections ⚕	—
R-HSA-9678108	SARS-CoV-1 Infection ⚕	—
R-HSA-9694516	SARS-CoV-2 Infection ⚕	—
R-HSA-9824446	Viral Infection Pathways ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-418990	Adherens junctions interactions	—
R-HSA-1236975	Antigen processing-Cross presentation	—
R-HSA-446728	Cell junction organization	—
R-HSA-1500931	Cell-Cell communication	—
R-HSA-421270	Cell-cell junction organization	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-1474290	Collagen formation	—
R-HSA-1236977	Endosomal/Vacuolar pathway	electronic
R-HSA-1474244	Extracellular matrix organization	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-1630316	Glycosaminoglycan metabolism	—
R-HSA-1638091	Heparan sulfate/heparin (HS-GAG) metabolism	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-1430728	Metabolism	—
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-9764265	Regulation of CDH1 Expression and Function	—
R-HSA-9764561	Regulation of CDH1 Function	—
R-HSA-9764274	Regulation of Expression and Function of Type I Classical Cadherins	—
R-HSA-9759476	Regulation of Homotypic Cell-Cell Adhesion	—
R-HSA-168898	Toll-like Receptor Cascades	—
R-HSA-8878171	Transcriptional regulation by RUNX1	—

MSigDB gene sets: 389 (showing top): MODULE_172, LEE_SP4_THYMOCYTE, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_SECRETORY_GRANULE, GOBP_ALPHA_BETA_T_CELL_DIFFERENTIATION, GOBP_MEMBRANE_FUSION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, MODULE_128, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (19): adaptive immune response (GO:0002250), proteolysis (GO:0006508), protein autoprocessing (GO:0016540), fusion of virus membrane with host plasma membrane (GO:0019064), receptor-mediated endocytosis of virus by host cell (GO:0019065), antigen processing and presentation (GO:0019882), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), collagen catabolic process (GO:0030574), zymogen activation (GO:0031638), enkephalin processing (GO:0034230), fusion of virus membrane with host endosome membrane (GO:0039654), CD4-positive, alpha-beta T cell lineage commitment (GO:0043373), symbiont entry into host cell (GO:0046718), antigen processing and presentation of peptide antigen (GO:0048002), elastin catabolic process (GO:0060309), macrophage apoptotic process (GO:0071888), cellular response to thyroid hormone stimulus (GO:0097067), extracellular matrix disassembly (GO:0022617), protein catabolic process (GO:0030163)

GO Molecular Function (10): fibronectin binding (GO:0001968), cysteine-type endopeptidase activity (GO:0004197), collagen binding (GO:0005518), cysteine-type peptidase activity (GO:0008234), histone binding (GO:0042393), proteoglycan binding (GO:0043394), serpin family protein binding (GO:0097655), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (13): extracellular region (GO:0005576), nucleus (GO:0005634), lysosome (GO:0005764), multivesicular body (GO:0005771), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), extracellular matrix (GO:0031012), endolysosome lumen (GO:0036021), chromaffin granule (GO:0042583), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), endocytic vesicle lumen (GO:0071682), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

16 top-level categories:

Category	Pathways
Extracellular matrix organization	2
Antigen processing-Cross presentation	1
Degradation of the extracellular matrix	1
Toll-like Receptor Cascades	1
Collagen formation	1
Heparan sulfate/heparin (HS-GAG) metabolism	1
Adaptive Immune System	1
Transcriptional regulation by RUNX1	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1
Regulation of CDH1 Function	1
Activation of STAT3 by cadherin engagement	1
Affinity selection of immunoglobulins	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Metabolism of carbohydrates and carbohydrate derivatives	1

GO top-level categories

60 GO namespaces:

Category	Terms
protein binding	4
protein metabolic process	2
protein processing	2
membrane fusion involved in viral entry into host cell	2
immune response	1
membrane fusion	1
receptor-mediated endocytosis	1
symbiont entry into host cell	1
endocytosis involved in viral entry into host cell	1
immune system process	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
catabolic process	1
collagen metabolic process	1
peptide hormone processing	1
alpha-beta T cell lineage commitment	1
CD4-positive, alpha-beta T cell differentiation	1
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1
viral life cycle	1
symbiont entry into host	1
antigen processing and presentation	1
glycoprotein catabolic process	1
elastin metabolic process	1
inflammatory cell apoptotic process	1
myeloid cell apoptotic process	1
leukocyte apoptotic process	1
cellular response to hormone stimulus	1
response to thyroid hormone	1
cellular component disassembly	1
extracellular matrix organization	1
macromolecule catabolic process	1
endopeptidase activity	1
cysteine-type peptidase activity	1
protein-containing complex binding	1
peptidase activity	1
carbohydrate derivative binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
lytic vacuole	1
late endosome	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
external encapsulating structure	1
endosome lumen	1
endolysosome	1
lysosomal lumen	1
secretory granule	1
lysosome	1
vacuolar lumen	1
extracellular vesicle	1
endocytic vesicle	1
intracellular organelle lumen	1
cytoplasm	1
intracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 22 of 44 annotations. The rest are phylogenetic / computational / electronic (IEA).

22 experimentally-supported GO terms:

GO term	NS	Evidence
adaptive immune response	BP	expression pattern
cellular response to thyroid hormone stimulus	BP	expression pattern
collagen catabolic process	BP	direct assay
fusion of virus membrane with host endosome membrane	BP	direct assay
fusion of virus membrane with host plasma membrane	BP	direct assay
protein autoprocessing	BP	direct assay
proteolysis	BP	direct assay
receptor-mediated endocytosis of virus by host cell	BP	direct assay
symbiont entry into host cell	BP	direct assay
zymogen activation	BP	direct assay
extracellular exosome	CC	high-throughput assay
extracellular matrix	CC	high-throughput assay
lysosome	CC	direct assay
multivesicular body	CC	direct assay
plasma membrane	CC	direct assay
collagen binding	MF	direct assay
cysteine-type endopeptidase activity	MF	direct assay
cysteine-type peptidase activity	MF	direct assay
fibronectin binding	MF	physical interaction
histone binding	MF	direct assay
proteoglycan binding	MF	physical interaction
serpin family protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 16 of 2,452 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTSL	TMPRSS2	O15393	893
CTSL	CST7	O76096	855
CTSL	LGMN	Q99538	843
CTSL	FURIN	P09958	820
CTSL	ACE2	Q9BYF1	820
CTSL	CTSD	P07339	789
CTSL	PSAP	P07292	681
CTSL	DNM2	P50570	607
CTSL	TMPRSS4	Q9NRS4	602
CTSL	LAMP1	P11279	597
CTSL	TMPRSS11D	O60235	580
CTSL	IL1B	P01584	577
CTSL	TMPRSS11A	Q6ZMR5	573
CTSL	BSG	P35613	570
CTSL	TYRP1	P17643	570
CTSL	FBXO32	Q969P5	570

IntAct

Human interaction partners of CTSL in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
CTSV	physical association	0.720	4
S	protein cleavage	0.620	5
SGTA	physical association	0.560	3
CST7	association	0.530	1
CTSH	association	0.530	1
BTN3A3	physical association	0.370	1
CRELD2	physical association	0.370	1
EED	physical association	0.370	1
PPP1CC	physical association	0.370	1
RELB	physical association	0.370	1
CSTB	association	0.350	1
KNG1	association	0.350	1
GEM	physical association	0.000	1
RSPH1	physical association	0.000	1

BioGRID (298 interactions; top human partners by supporting records): CCDC88A (Affinity Capture-MS; 3 records), CLTCL1 (Affinity Capture-MS; 3 records), CSTA (Reconstituted Complex; 3 records), CTSH (Affinity Capture-MS; 3 records), CTSL3P (Affinity Capture-MS; 3 records), CTSV (Affinity Capture-MS; 3 records), IGF2R (Affinity Capture-MS; 3 records), SERPINB3 (Reconstituted Complex; 3 records), AIMP1 (Affinity Capture-MS; 2 records), APP (Affinity Capture-MS; 2 records), BAG2 (Affinity Capture-MS; 2 records), CALM2 (Affinity Capture-MS; 2 records), CALR (Affinity Capture-MS; 2 records), CALU (Affinity Capture-MS; 2 records), CLGN (Affinity Capture-MS; 2 records)

SIGNOR signaling

showing 4 of 6 signaling interactions:

A	Effect	B	Mechanism
aloxistatin	“down-regulates activity”	CTSL	“chemical inhibition”
CTSL	“up-regulates activity”	S	cleavage
CTSL	“down-regulates quantity by destabilization”	BGLAP	cleavage
NSFL1C	“down-regulates activity”	CTSL	binding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ CD74-CTSL complex	2	CD74, CTSL

Disease & clinical

Genetic variants

Variant evidence for CTSL: 62 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

62 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	4
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 670):

Position(s)	Effect	Δscore	Sites
9:87726188	donor_gain	1.0000
9:87728150–87728151	donor_loss	1.0000	5
9:87728228	acceptor_gain	1.0000
9:87728245	acceptor_gain	1.0000
9:87728397–87728398	donor_loss	1.0000	5
9:87729567	acceptor_gain	1.0000
9:87729571	acceptor_gain	1.0000
9:87729572	acceptor_loss	1.0000	2
9:87729736–87729737	donor_loss	1.0000	4
9:87731006	acceptor_loss	1.0000	2

AlphaMissense

881 missense substitutions predicted likely pathogenic (of 2,231 scored), across 198 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H276	8	0.977	0.990
N300	8	0.971	0.994
F141	8	0.968	0.998
S162	8	0.943	0.995
S301	8	0.935	0.985
D82	8	0.921	0.962
D168	8	0.911	0.969
F256	8	0.897	0.973
S142	8	0.894	0.996
N78	8	0.841	0.980
D184	8	0.837	0.938
D250	8	0.831	0.929
M183	8	0.808	0.905
H62	8	0.799	0.954
C322	7	0.989	0.997
C135	7	0.981	0.993
C169	7	0.981	0.989
W139	7	0.979	0.995
F187	7	0.978	0.988
C269	7	0.978	0.989

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	4.43e-11
Glioblastoma Multiforme (TCGA)	unfavorable	4.25e-07
Lung Adenocarcinoma (TCGA)	unfavorable	6.88e-05
Head and Neck Squamous Cell Carcinoma (TCGA)	unfavorable	0.00042

Disease associations

OMIM: gene MIM:116880 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST003542_13	Night sleep phenotypes	5e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111380 (SELECTIVITY GROUP), CHEMBL3837 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 56,380 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

11 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL218394	BOCEPREVIR	4	2,896
CHEMBL231813	TELAPREVIR	4	3,453
CHEMBL590799	CAMOSTAT	3	6,825
CHEMBL481611	ODANACATIB	3	828
CHEMBL359965	ALLICIN	2	14,925
CHEMBL63440	ALOXISTATIN	2	758
CHEMBL5095230	ATUZAGINSTAT	2	75
CHEMBL371064	BALICATIB	2	99
CHEMBL91704	K-777	2	213
CHEMBL296588	PEPSTATIN	2	26,189
CHEMBL203665	RELACATIB	2	119

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C1: Papain

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
AC1115	Inhibition	10.22	pIC50
MG-101	Inhibition	10.19	pKi
VBY-825	Inhibition	9.6	pKi
D6-3	Inhibition	9.57	pIC50
CAA0225	Inhibition	8.7	pIC50
GC-376	Inhibition	8.36	pIC50
LHVS	Inhibition	8.15	pIC50
compound 1 [PMID: 40415551]	Inhibition	7.54	pIC50
K11777	Inhibition	7.3	pKi
KGP94	Inhibition	6.9	pIC50
Mpro inhibitor 13b	Inhibition	6.53	pKi
compound 4d [PMID: 38746883]	Inhibition	6.15	pIC50
UAWJ9-36-3	Inhibition	5.74	pIC50

Binding affinities (BindingDB)

1838 measured of 2691 human assays (3088 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[2-(1H-imidazol-1-yl)ethoxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.003 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.003 nM
2-cyano-4-(cyclohexylamino)-N-[2-(3-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	IC50	0.009 nM
2-cyano-4-(cyclohexylamino)-N-(2-phenylethyl)pyrimidine-5-carboxamide	IC50	0.01 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[3-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.011 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.011 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.013 nM
2-cyano-4-(cyclohexylamino)-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	IC50	0.022 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.025 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-(2-{3-[2-(1H-imidazol-1-yl)ethoxy]-4-methoxyphenyl}ethyl)pyrimidine-5-carboxamide	IC50	0.031 nM
2-cyano-4-(cyclohexylamino)-N-{2-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.047 nM
(1S)-2-cyclohexyl-1-methylethyl 2-cyano-2-methylhydrazinecarboxylate	KI	0.077 nM
CHEMBL2207565	IC50	0.1 nM
CHEMBL2207564	IC50	0.1 nM
(2S)-2-(1-benzofuran-2-ylformamido)-4-methyl-N-[(4S,6S)-6-methyl-3-oxo-1-(pyridine-2-sulfonyl)azepan-4-yl]pentanamide	KI	0.14 nM
CHEMBL4596647	IC50	0.149 nM
(1S)-1-benzylpropyl 2-cyano-2-methylhydrazinecarboxylate	KI	0.25 nM
CHEMBL4594870	IC50	0.278 nM
2-cyano-4-[(2,2-dimethylpropyl)amino]-N-{2-[4-(pyrrolidin-1-yl)phenyl]ethyl}pyrimidine-5-carboxamide	IC50	0.3 nM
CHEMBL2207562	IC50	0.3 nM
CHEMBL6083070	IC50	0.3 nM
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.322 nM	US-9409882: Pyridine derivatives
N-{4-[5-(2-Thienyl)-1,2,4-oxadiazol-3-yl]benzoyl}-leucyl-methylazalanine-nitrile	KI	0.36 nM
CHEMBL6091804	IC50	0.36 nM
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.375 nM	US-9409882: Pyridine derivatives
tert-butyl 2-[(2S,4R)-4-(2-chloro-4-fluorophenyl)sulfonyl-2-[(1-cyanocyclopropyl)carbamoyl]pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-2-pyridinyl)azetidine-1-carboxylate	IC50	0.377 nM	US-8822505: Azetidine derivatives
N-(Benzyloxycarbonyl)-tyrosyl-methylazalanine-nitrile	KI	0.38 nM
(2S,4R)-4-[2-chloro-4-(2-methyl-3-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)-1-[1-(3-fluoro-5-iodo-2-pyridinyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide	IC50	0.382 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chloro-4-methoxyphenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.393 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.398 nM	US-9409882: Pyridine derivatives
acs.jmedchem.1c00409_ST.412	KI	0.406 nM
CHEMBL6078112	IC50	0.41 nM
CHEMBL4594757	IC50	0.416 nM
(S)-benzyl 1-(2-cyano-1,2-dimethylhydrazinyl)-4-methyl-1-oxopentan-2-ylcarbamate	KI	0.43 nM
(2S,4R)-1-[1-(5-bromo-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.438 nM	US-9409882: Pyridine derivatives
acs.jmedchem.1c00409_ST.413	KI	0.459 nM
(2S,4R)-4-(4-bromo-2-chlorophenyl)sulfonyl-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.474 nM	US-9409882: Pyridine derivatives
N-(Benzyloxycarbonyl)-cyclohexylalanyl-methylazalanine-nitrile	KI	0.48 nM
tert-butyl 2-(5-bromo-3-fluoro-2-pyridinyl)-2-[(2S,4R)-4-(2-chloro-4-fluorophenyl)sulfonyl-2-[(1-cyanocyclopropyl)carbamoyl]pyrrolidine-1-carbonyl]azetidine-1-carboxylate	IC50	0.492 nM	US-8822505: Azetidine derivatives
(2S,4R)-4-(2-chlorophenyl)sulfonyl-1-[1-(5-chloro-2-pyridinyl)cyclopropanecarbonyl]-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.492 nM	US-9409882: Pyridine derivatives
CHEMBL2207563	IC50	0.5 nM
CHEMBL6083027	IC50	0.5 nM
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-4-(2-methyl-4-pyridinyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.505 nM	US-9409882: Pyridine derivatives
(2S,4R)-1-[3-(5-bromo-3-fluoro-2-pyridinyl)-1-methylazetidine-3-carbonyl]-4-(2-chlorophenyl)sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.525 nM	US-8822505: Azetidine derivatives
(2S,4R)-1-[1-(5-chloro-3-fluoro-2-pyridinyl)cyclopropanecarbonyl]-4-[2-chloro-5-(trifluoromethyl)phenyl]sulfonyl-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide	IC50	0.543 nM	US-9409882: Pyridine derivatives
N-[(1S)-2-[(3aS,6R,6aR)-6-ethynyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-1-cyclopentyl-2-oxoethyl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.6 nM	US-8735395: Protease inhibitors
N-[(1S)-1-cyclopentyl-2-[(6R)-6-ethynyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl]-2-oxoethyl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.6 nM	US-9200006: Protease inhibitors
(2S,4R)-N-(1-cyanocyclopropyl)-1-[1-(3-fluoro-5-iodo-2-pyridinyl)cyclopropanecarbonyl]-4-(2-fluorophenyl)sulfonylpyrrolidine-2-carboxamide	IC50	0.6 nM	US-9409882: Pyridine derivatives
N-[1-cyclopentyl-1-(6-ethynyl-3-oxo-3a,5,6,6a-tetrahydrofuro[3,2-b]pyrrol-4-yl)-2-oxoethyl]-4-[5-fluoro-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]benzamide	KI	0.6 nM	US-10723709: Protease inhibitors
CHEMBL2207571	IC50	0.6 nM

ChEMBL bioactivities

2023 potent at pChembl≥5 of 2286 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.60	Ki	0.025	nM	CHEMBL190121
10.44	Ki	0.036	nM	CHEMBL191558
10.40	Ki	0.04	nM	CHEMBL202668
10.35	Ki	0.045	nM	CHEMBL1651355
10.31	Ki	0.049	nM	CHEMBL286722
10.19	Ki	0.0645	nM	CHEMBL304784
10.17	Ki	0.068	nM	RELACATIB
10.03	IC50	0.094	nM	CHEMBL4441303
10.00	IC50	0.1	nM	CHEMBL31788
10.00	IC50	0.1	nM	CHEMBL287630
9.90	Ki	0.1259	nM	CHEMBL4212454
9.82	IC50	0.15	nM	MG-132
9.80	Ki	0.16	nM	CHEMBL604281
9.77	IC50	0.17	nM	CHEMBL218024
9.70	IC50	0.2	nM	K-777
9.66	Ki	0.22	nM	CHEMBL1651361
9.60	Ki	0.2512	nM	CHEMBL4755248
9.60	IC50	0.25	nM	CHEMBL3427166
9.52	IC50	0.3	nM	CHEMBL6083070
9.51	IC50	0.31	nM	CHEMBL385632
9.48	IC50	0.33	nM	CHEMBL374890
9.48	IC50	0.3311	nM	CHEMBL6190904
9.47	IC50	0.34	nM	CHEMBL220496
9.44	IC50	0.36	nM	CHEMBL6091804
9.44	Ki	0.36	nM	CHEMBL1651353
9.41	Ki	0.39	nM	CHEMBL1651354
9.40	Ki	0.4	nM	CHEMBL4078345
9.40	Ki	0.4	nM	CHEMBL1651352
9.39	IC50	0.41	nM	CHEMBL6078112
9.37	Ki	0.43	nM	CHEMBL194643
9.36	IC50	0.437	nM	CHEMBL492175
9.35	IC50	0.45	nM	CHEMBL219536
9.33	Ki	0.47	nM	CHEMBL177914
9.31	Ki	0.49	nM	CHEMBL284939
9.30	Ki	0.5012	nM	CHEMBL4746022
9.30	Ki	0.5012	nM	CHEMBL4217414
9.30	IC50	0.5	nM	CHEMBL6083027
9.28	IC50	0.52	nM	CHEMBL218007
9.28	IC50	0.53	nM	CHEMBL1807649
9.24	Ki	0.57	nM	CHEMBL194861
9.24	IC50	0.58	nM	CHEMBL436303
9.22	Ki	0.6	nM	CHEMBL48837
9.22	Ki	0.6	nM	CHEMBL4584291
9.21	Ki	0.61	nM	CHEMBL4083754
9.20	Ki	0.63	nM	CHEMBL205172
9.20	IC50	0.632	nM	CHEMBL4447348
9.20	Ki	0.631	nM	CHEMBL4744431
9.19	Ki	0.64	nM	CHEMBL132586
9.17	IC50	0.68	nM	CHEMBL384685
9.17	IC50	0.68	nM	K-777

PubChem BioAssay actives

2075 with measured affinity, of 4142 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[(2S)-4-methyl-1-[[(4S,5S)-5-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]-1-benzofuran-2-carboxamide	1797898: Enzyme Inhibition Assay from Article 10.1021/jm050915u: “Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.”	ki	<0.0001	uM
[(2S)-1-cyclohexylpropan-2-yl] N-[cyano(methyl)amino]carbamate	238799: Inhibition constant against human cathepsin L using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
[(2S)-1-phenylbutan-2-yl] N-[cyano(methyl)amino]carbamate	238813: Inhibition constant against human cathepsin L using Cbz-Phe-Arg-AMC	ki	<0.0001	uM
1-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-3-phenylurea	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	<0.0001	uM
benzyl N-[(2S)-3-methyl-1-oxo-1-[[(2S)-1-oxo-3-phenylpropan-2-yl]amino]butan-2-yl]carbamate	2105686: Inhibition of Cathepsin L (unknown origin) assessed as inhibition constant using Z-RR-AMC as fluorogenic substrate by fluorescence based microplate analysis	ki	<0.0001	uM
benzyl N-[(2S)-1-[[(2S,3R)-2-(benzenesulfonyl)-4-oxoazetidin-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	51218: Inhibition of recombinant human Cathepsin L	ic50	0.0001	uM
benzyl N-[(2S)-1-oxo-1-[[(3R,4S)-2-oxo-4-phenylsulfanylazetidin-3-yl]amino]-3-phenylpropan-2-yl]carbamate	51218: Inhibition of recombinant human Cathepsin L	ic50	0.0001	uM
3-tert-butyl-N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-1-oxo-3-phenylpropan-2-yl]-1-methylpyrazole-5-carboxamide	1698844: Inhibition of human cathepsin L using Z-Phe-Arg-7-amido-4-methylcoumarin as substrate preincubated for 2 mins followed by substrate addition by fluorimetric assay	ki	0.0001	uM
[(2S)-1-[[(2S)-1-[[(E,2S)-5-[(2S)-3-methoxy-2-(2-methylpropyl)-5-oxo-2H-pyrrol-1-yl]-5-oxo-1-phenylpent-3-en-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl] (2S,3S)-2-(dimethylamino)-3-methylpentanoate	1526361: Inhibition of human cathepsin L using fluorogenic substrate cbz-FR-AMC monitored for 90 to 120 mins by spectrophotometry	ic50	0.0001	uM
(2S)-2-acetamido-4-methyl-N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxohexan-2-yl]amino]pentan-2-yl]pentanamide	2105686: Inhibition of Cathepsin L (unknown origin) assessed as inhibition constant using Z-RR-AMC as fluorogenic substrate by fluorescence based microplate analysis	ki	0.0001	uM
benzyl N-[(2S)-4-methyl-1-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]carbamate	1922129: Inhibition of Cathepsin L (unknown origin) preincubated for 30 mins followed by fluorogenic substrate addition and measured for 15 mins by fluorescence microplate reader analysis	ic50	0.0001	uM
N-[(2S)-4-methyl-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]-1-benzofuran-2-carboxamide	1797898: Enzyme Inhibition Assay from Article 10.1021/jm050915u: “Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.”	ki	0.0001	uM
2-cyano-4-(cyclohexylamino)-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0002	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-1-oxo-3-phenylpropan-2-yl]carbamate	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0002	uM
N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-4-(5-thiophen-2-yl-1,2,4-oxadiazol-3-yl)benzamide	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0002	uM
N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]-4-methylpiperazine-1-carboxamide	1561237: Inhibition of human Cathepsin L using Cbz-Phe-Arg-AMC as substrate by fluorescence assay	ic50	0.0002	uM
sodium (2S)-1-hydroxy-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate	1871201: Inhibition of human cathepsin L	ic50	0.0003	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0003	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0003	uM
2-cyano-4-(cyclohexylamino)-N-[2-(3-methoxyphenyl)ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0003	uM
(2S)-2-[(3-bromophenyl)sulfonylamino]-3-(3-chlorophenyl)-N-[(1R,2R)-1-cyano-2-phenylmethoxypropyl]propanamide	1683750: Inhibition of human cathepsin L	ki	0.0003	uM
N-[(2S)-3-(3-fluorophenyl)-1-oxo-1-[[(3S)-2-oxo-5-(5-oxo-4H-1,2,4-triazol-1-yl)-1-[2,3,5,6-tetrafluoro-4-(2-hydroxypropan-2-yl)phenoxy]pentan-3-yl]amino]propan-2-yl]-4-methoxy-1H-indole-2-carboxamide	2279603: Inhibition of recombinant human cathepsin L using Z-Leu-Arg-AMC as substrate preincubated for 10 mins followed by substrate addition and measured after 10 mins by fluorescence spectrophotometric analysis	ic50	0.0003	uM
sodium (2S)-2-[[(2S)-2-[(3-fluorophenyl)methoxycarbonylamino]-4-methylpentanoyl]amino]-1-hydroxy-4-methylpentane-1-sulfonate	2205597: Inhibition of human cathepsin L using Z-Phe-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition and measured for 1 hr by plate reader assay	ic50	0.0003	uM
N-[(2S)-3-cycloheptyl-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopropan-2-yl]furan-2-carboxamide	609674: Inhibition of human recombinant cathepsin L using Z-LR-AMC as substrate by fluorescence assay	ic50	0.0004	uM
N-[(2S)-3-naphthalen-2-yl-1-oxo-1-[[(4S)-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]propan-2-yl]naphthalene-1-carboxamide	255214: Apparent inhibitory constant against human cathepsin L	ki	0.0004	uM
benzyl N-[(2S)-1-oxo-1-[[(E,3S)-6-oxo-1-phenylhept-4-en-3-yl]amino]-3-phenylpropan-2-yl]carbamate	1458683: Inhibition of human cathepsin L using Cbz-Phe-Arg-AMC as substrate after 10 mins by fluorescence assay	ki	0.0004	uM
2-cyano-4-(cyclohexylamino)-N-[2-[4-(4-methylpiperazin-1-yl)phenyl]ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0004	uM
sodium (2S)-1-hydroxy-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methylpentanoyl]amino]-4-methylpentane-1-sulfonate	2205597: Inhibition of human cathepsin L using Z-Phe-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition and measured for 1 hr by plate reader assay	ic50	0.0004	uM
sodium (2S)-3-cyclobutyl-1-hydroxy-2-[[(2S)-2-[(4-methoxy-1H-indole-2-carbonyl)amino]-4-methylpentanoyl]amino]propane-1-sulfonate	2205597: Inhibition of human cathepsin L using Z-Phe-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition and measured for 1 hr by plate reader assay	ic50	0.0004	uM
3-acetyl-8-chloro-2-(4-chloroanilino)-6-nitro-1H-quinolin-4-one	350738: Inhibition of human liver cathepsin L after 30 mins by fluorometric end-point assay	ic50	0.0004	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-3-cyclohexyl-1-oxopropan-2-yl]carbamate	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0004	uM
benzyl N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamate	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0004	uM
1-benzyl-3-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]urea	554254: Inhibition of human recombinant cathepsin L after 30 mins by spectrophotometric assay	ki	0.0004	uM
benzyl N-[(2S)-1-[[(2S)-1-(4-hydroxyphenyl)-3-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	255214: Apparent inhibitory constant against human cathepsin L	ki	0.0005	uM
3-tert-butyl-N-[(2S)-1-[[cyano(methyl)amino]-methylamino]-4-methyl-1-oxopentan-2-yl]-1-methylpyrazole-5-carboxamide	1698844: Inhibition of human cathepsin L using Z-Phe-Arg-7-amido-4-methylcoumarin as substrate preincubated for 2 mins followed by substrate addition by fluorimetric assay	ki	0.0005	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[4-(2-imidazol-1-ylethoxy)phenyl]ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0005	uM
N-[(2S)-3-(3-bromophenyl)-1-[[(1R,2R)-1-cyano-2-phenylmethoxypropyl]amino]-1-oxopropan-2-yl]-3-tert-butyl-1-methylpyrazole-5-carboxamide	1683750: Inhibition of human cathepsin L	ki	0.0005	uM
sodium (2S)-3-cyclobutyl-2-[[(2S)-2-[(3-fluorophenyl)methoxycarbonylamino]-4-methylpentanoyl]amino]-1-hydroxypropane-1-sulfonate	2205597: Inhibition of human cathepsin L using Z-Phe-Arg-AMC as substrate preincubated for 30 mins followed by substrate addition and measured for 1 hr by plate reader assay	ic50	0.0005	uM
N-[(2S)-4-methyl-1-oxo-1-[[(4S)-3-oxo-1-[2-(3-pyridin-2-ylphenyl)acetyl]azepan-4-yl]amino]pentan-2-yl]-5-(2-morpholin-4-ylethoxy)-1-benzofuran-2-carboxamide	219375: Inhibitory activity against Human cathepsin L	ki	0.0005	uM
N-[(2S)-4-methyl-1-[[(4S,7R)-7-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]furan-2-carboxamide	609674: Inhibition of human recombinant cathepsin L using Z-LR-AMC as substrate by fluorescence assay	ic50	0.0005	uM
benzyl N-[(2S)-1-[[(2S)-1-(4-butoxyphenyl)-3,4-dioxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamate	51355: Ability to block cathepsin L-catalyzed hydrolysis of the fluorogenic substrate Z-Phe-Arg-NHMec	ki	0.0006	uM
N-[(2S)-3-naphthalen-2-yl-1-oxo-1-[[(4S)-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]propan-2-yl]-1-benzofuran-2-carboxamide	255214: Apparent inhibitory constant against human cathepsin L	ki	0.0006	uM
N-[(2S)-4-methyl-1-[[(4S,6S)-6-methyl-3-oxo-1-pyridin-2-ylsulfonylazepan-4-yl]amino]-1-oxopentan-2-yl]-1-benzofuran-2-carboxamide	1797898: Enzyme Inhibition Assay from Article 10.1021/jm050915u: “Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.”	ki	0.0006	uM
benzyl N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate	1458683: Inhibition of human cathepsin L using Cbz-Phe-Arg-AMC as substrate after 10 mins by fluorescence assay	ki	0.0006	uM
[(2S)-1-[[(2S)-1-[[(E,2S)-5-[(2S)-3-methoxy-2-(2-methylpropyl)-5-oxo-2H-pyrrol-1-yl]-5-oxo-1-phenylpent-3-en-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl] (2S)-2-(dimethylamino)-3-methylbutanoate	1526361: Inhibition of human cathepsin L using fluorogenic substrate cbz-FR-AMC monitored for 90 to 120 mins by spectrophotometry	ic50	0.0006	uM
4-chloro-N-[(2S)-1-oxo-1-[[(E,3S)-6-oxo-1-phenylhept-4-en-3-yl]amino]-3-phenylpropan-2-yl]benzamide	1541383: Inhibition of human Cathepsin L assessed as inhibition constant using Cbz-Phe-Arg-AMC as substrate by fluorescence assay	ki	0.0006	uM
2-cyano-4-(2,2-dimethylpropylamino)-N-[2-[3-(2-imidazol-1-ylethoxy)-4-methoxyphenyl]ethyl]pyrimidine-5-carboxamide	1797894: Enzyme Inhibition Assay from Article 10.1021/jm0613525: “2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K.”	ic50	0.0006	uM
3-bromo-N-[(2S)-3-(3-chlorophenyl)-1-[[(1R,2R)-1-cyano-2-phenylmethoxypropyl]amino]-1-oxopropan-2-yl]benzamide	1683750: Inhibition of human cathepsin L	ki	0.0006	uM
benzyl N-[1-[[1,2-dioxo-1-(pyridin-2-ylmethylamino)hexan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate	2105686: Inhibition of Cathepsin L (unknown origin) assessed as inhibition constant using Z-RR-AMC as fluorogenic substrate by fluorescence based microplate analysis	ki	0.0006	uM
N’-(5-bromo-2-cyanopyrimidin-4-yl)-4-[(4-methylpiperazin-1-yl)methyl]-N’-(2-methylpropyl)benzohydrazide	1391660: Inhibition of human cathepsin L	ic50	0.0007	uM

CTD chemical–gene interactions

119 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression, affects expression	8
Valproic Acid	affects cotreatment, increases expression, affects expression	7
bisphenol A	decreases expression, increases expression, affects expression	4
Cyclosporine	decreases activity, increases expression	4
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	3
Tobacco Smoke Pollution	increases expression	3
Cadmium Chloride	decreases reaction, increases cleavage, increases abundance, increases palmitoylation, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
nickel sulfate	decreases expression, increases expression	2
Decitabine	affects expression, increases expression	2
Arsenic Trioxide	affects binding, decreases reaction, affects response to substance, increases abundance, affects expression	2
Cisplatin	affects expression, decreases response to substance	2
Ivermectin	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
Paclitaxel	decreases response to substance, increases response to substance	2
tert-Butylhydroperoxide	increases expression, decreases expression	2
GSK-J4	increases expression	1
GSK2795039	affects reaction, decreases cleavage	1
TAK-243	increases sumoylation	1
sotorasib	decreases expression, affects cotreatment	1
tannic acid	decreases expression	1
dicrotophos	decreases expression	1
beta-N-methylamino-L-alanine	affects cotreatment, increases activity	1
2,4,6-tribromophenol	decreases expression	1
2,4-diaminobutyric acid	affects cotreatment, increases activity	1
lead acetate	increases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
asperphenamate	affects binding, decreases activity	1

ChEMBL screening assays

521 unique, capped per target: 494 binding, 11 admet, 8 toxicity, 8 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5106296	Binding	Selectivity ratio of IC50 for Cathepsin L (unknown origin) to IC50 for Cathepsin K (unknown origin)	Lead optimization of cathepsin K inhibitors for the treatment of Osteoarthritis. — *Bioorg Med Chem Lett*
CHEMBL4322235	ADMET	Inhibition of human cathepsin L assessed as ratio of Kcat/Km using Z-Phe-Arg-MCA as substrate by spectrofluorometric method	Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity? — *J Med Chem*
CHEMBL5154227	Toxicity	Inhibition of human cathepsin L using Z-Leu-Arg-AMC as substrate by FRET assay	Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors. — *J Med Chem*

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2VF	Abcam HEK293T CTSL KO	Transformed cell line	Female
CVCL_D7N5	Ubigene A-549 CTSL KO	Cancer cell line	Male
CVCL_F6E2	EDITGENE CSTL Knockout HEK293 Cell Line	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CTSL across ~30M SureChEMBL compounds — explore on Sugi Predict.