Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8WVIBW)

• DOT Name: Retroviral-like aspartic protease 1 (ASPRV1)
• Synonyms: EC 3.4.23.-; Skin-specific retroviral-like aspartic protease; SASPase; Skin aspartic protease; TPA-inducible aspartic proteinase-like protein; TAPS
• Gene Name: ASPRV1
• Related Disease:
  Pulmonary disease
  Advanced cancer
  Colitis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Ichthyosis, lamellar, autosomal dominant
  Non-syndromic ichthyosis
  Osteoarthritis
  Precancerous condition
  Pulmonary fibrosis
  Squamous cell carcinoma
  Ulcerative colitis
  Autoimmune polyendocrinopathy
  Fetal growth restriction
  Generalized anxiety disorder
  Nervous system inflammation
  Polycythemia
• UniProt ID: APRV1_HUMAN
• EC Number: 3.4.23.-
• Pfam ID: PF13975
• Sequence:
  MGSPGASLGIKKALQSEQATALPASAPAVSQPTAPAPSCLPKAGQVIPTLLREAPFSSVI
  APTLLCGFLFLAWVAAEVPEESSRMAGSGARSEEGRRQHAFVPEPFDGANVVPNLWLHSF
  EVINDLNHWDHITKLRFLKESLRGEALGVYNRLSPQDQGDYGTVKEALLKAFGVPGAAPS
  HLPKEIVFANSMGKGYYLKGKIGKVPVRFLVDSGAQVSVVHPNLWEEVTDGDLDTLQPFE
  NVVKVANGAEMKILGVWDTAVSLGKLKLKAQFLVANASAEEAIIGTDVLQDHNAILDFEH
  RTCTLKGKKFRLLPVGGSLEDEFDLELIEEDPSSEEGRQELSH
• Function: Protease responsible for filaggrin processing, essential for the maintenance of a proper epidermis organization.
• Tissue Specificity: Expressed primarily in the granular layer of the epidermis and inner root sheath of hair follicles. In psoriatic skin, expressed throughout the stratum corneum. In ulcerated skin, expressed in the stratum granulosum of intact epidermis but almost absent from ulcerated regions. Expressed in differentiated areas of squamous cell carcinomas but not in undifferentiated tumors.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary disease	DIS6060I	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Ichthyosis, lamellar, autosomal dominant	DISY9ICJ	Strong	Autosomal dominant	[6]
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Biomarker	[7]
Osteoarthritis	DIS05URM	Strong	Biomarker	[8]
Precancerous condition	DISV06FL	Strong	Biomarker	[9]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[11]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[12]
Autoimmune polyendocrinopathy	DISOLDB2	Limited	Biomarker	[13]
Fetal growth restriction	DIS5WEJ5	Limited	Altered Expression	[14]
Generalized anxiety disorder	DISPSQCW	Limited	Biomarker	[15]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[16]
Polycythemia	DIS8B6VW	Limited	Altered Expression	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Retroviral-like aspartic protease 1 (ASPRV1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retroviral-like aspartic protease 1 (ASPRV1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Retroviral-like aspartic protease 1 (ASPRV1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Retroviral-like aspartic protease 1 (ASPRV1).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Retroviral-like aspartic protease 1 (ASPRV1).	[19]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Retroviral-like aspartic protease 1 (ASPRV1).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Retroviral-like aspartic protease 1 (ASPRV1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Retroviral-like aspartic protease 1 (ASPRV1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Retroviral-like aspartic protease 1 (ASPRV1).	[25]

References

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• [2] Ly6G(+) inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model.Cell Death Differ. 2019 Oct;26(10):2139-2156. doi: 10.1038/s41418-019-0282-0. Epub 2019 Feb 25.
• [3] Schiff base complexes of copper and zinc as potential anti-colitic compounds.Biometals. 2017 Jun;30(3):423-439. doi: 10.1007/s10534-017-0016-z. Epub 2017 Apr 19.
• [4] Tumor cell-secreted PLD increases tumor stemness by senescence-mediated communication with microenvironment.Oncogene. 2019 Feb;38(8):1309-1323. doi: 10.1038/s41388-018-0527-2. Epub 2018 Oct 10.
• [5] Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments.Mol Oncol. 2019 Nov;13(11):2460-2475. doi: 10.1002/1878-0261.12577. Epub 2019 Oct 6.
• [6] Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis. Am J Hum Genet. 2020 Jul 2;107(1):158-163. doi: 10.1016/j.ajhg.2020.05.013. Epub 2020 Jun 8.
• [7] A de novo variant in the ASPRV1 gene in a dog with ichthyosis.PLoS Genet. 2017 Mar 1;13(3):e1006651. doi: 10.1371/journal.pgen.1006651. eCollection 2017 Mar.
• [8] Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development.Sci Transl Med. 2019 Apr 3;11(486):eaar6659. doi: 10.1126/scitranslmed.aar6659.
• [9] A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.PLoS One. 2010 Feb 12;5(2):e9188. doi: 10.1371/journal.pone.0009188.
• [10] Senolytic drugs targetalveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo.Eur Respir J. 2017 Aug 3;50(2):1602367. doi: 10.1183/13993003.02367-2016. Print 2017 Aug.
• [11] A novel aspartic proteinase-like gene expressed in stratified epithelia and squamous cell carcinoma of the skin.Am J Pathol. 2006 Apr;168(4):1354-64. doi: 10.2353/ajpath.2006.050871.
• [12] Molecular mechanisms by which casein glycomacropeptide maintains internal homeostasis in mice with experimental ulcerative colitis.PLoS One. 2017 Jul 10;12(7):e0181075. doi: 10.1371/journal.pone.0181075. eCollection 2017.
• [13] Pregnancy Outcome in Women with Obstetric and Thrombotic Antiphospholipid Syndrome-A Retrospective Analysis and a Review of Additional Treatment in Pregnancy.Clin Rev Allergy Immunol. 2017 Aug;53(1):54-67. doi: 10.1007/s12016-016-8569-0.
• [14] Fetal stroke and cerebrovascular disease: Advances in understanding from lenticulostriate and venous imaging, alloimmune thrombocytopaenia and monochorionic twins.Eur J Paediatr Neurol. 2018 Nov;22(6):989-1005. doi: 10.1016/j.ejpn.2018.08.008. Epub 2018 Sep 11.
• [15] Implementing electronic substance use disorder and depression and anxiety screening and behavioral interventions in primary care clinics serving people with HIV: Protocol for the Promoting Access to Care Engagement (PACE) trial.Contemp Clin Trials. 2019 Sep;84:105833. doi: 10.1016/j.cct.2019.105833. Epub 2019 Aug 22.
• [16] ICAM1+ neutrophils promote chronic inflammation via ASPRV1 in B cell-dependent autoimmune encephalomyelitis.JCI Insight. 2017 Dec 7;2(23):e96882. doi: 10.1172/jci.insight.96882.
• [17] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [20] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [23] 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.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.