Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT53QQ7N)

• DOT Name: Ubiquitin-like protein ISG15 (ISG15)
• Synonyms: Interferon-induced 15 kDa protein; Interferon-induced 17 kDa protein; IP17; Ubiquitin cross-reactive protein; hUCRP
• Gene Name: ISG15
• Related Disease: Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency
• UniProt ID: ISG15_HUMAN
• PDB ID: 1Z2M; 2HJ8; 3PHX; 3PSE; 3R66; 3RT3; 3SDL; 5TL6; 5W8T; 5W8U; 6BI8; 6FFA; 6XA9; 7RBS; 7S6P; 8SE9; 8SEA; 8SEB; 8SV8
• Pfam ID: PF00240
• Sequence:
  MGWDLTVKMLAGNEFQVSLSSSMSVSELKAQITQKIGVHAFQQRLAVHPSGVALQDRVPL
  ASQGLGPGSTVLLVVDKCDEPLSILVRNNKGRSSTYEVRLTQTVAHLKQQVSGLEGVQDD
  LFWLTFEGKPLEDQLPLGEYGLKPLSTVFMNLRLRGGGTEPGGRS
• Function: Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. Can also isgylate: EIF2AK2/PKR which results in its activation, RIGI which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL.
• Tissue Specificity: Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-cancerous tissue. In bladder cancer, the increase in expression exhibits a striking positive correlation with more advanced stages of the disease.
• KEGG Pathway:
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Human papillomavirus infection (hsa05165)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
  Termination of translesion DNA synthesis (R-HSA-5656169)
  Interferon alpha/beta signaling (R-HSA-909733)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  PKR-mediated signaling (R-HSA-9833482)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	DIS0BML0	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Ubiquitin-like protein ISG15 (ISG15) affects the response to substance of Paclitaxel.	[31]
Topotecan	DMP6G8T	Approved	Ubiquitin-like protein ISG15 (ISG15) affects the response to substance of Topotecan.	[31]
Mitoxantrone	DMM39BF	Approved	Ubiquitin-like protein ISG15 (ISG15) affects the response to substance of Mitoxantrone.	[31]

35 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 Ubiquitin-like protein ISG15 (ISG15).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ubiquitin-like protein ISG15 (ISG15).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[16]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[17]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[13]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ubiquitin-like protein ISG15 (ISG15).	[19]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[13]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[13]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[18]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[13]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[13]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Ubiquitin-like protein ISG15 (ISG15).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[22]
Lipoteichoic acid	DMEMRW0	Phase 1/2	Lipoteichoic acid increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ubiquitin-like protein ISG15 (ISG15).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[29]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ubiquitin-like protein ISG15 (ISG15).	[30]

1 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 decreases the methylation of Ubiquitin-like protein ISG15 (ISG15).	[24]

References

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