Details of Drug Off-Target (DOT)

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

• DOT Name: WD40 repeat-containing protein SMU1 (SMU1)
• Synonyms: Smu-1 suppressor of mec-8 and unc-52 protein homolog
• Gene Name: SMU1
• Related Disease:
  Chromosomal disorder
  Influenza
• UniProt ID: SMU1_HUMAN
• PDB ID: 5O9Z; 6AHD; 6Q8F; 6Q8I; 6Q8J
• Pfam ID: PF17814 ; PF00400
• Sequence:
  MSIEIESSDVIRLIMQYLKENSLHRALATLQEETTVSLNTVDSIESFVADINSGHWDTVL
  QAIQSLKLPDKTLIDLYEQVVLELIELRELGAARSLLRQTDPMIMLKQTQPERYIHLENL
  LARSYFDPREAYPDGSSKEKRRAAIAQALAGEVSVVPPSRLMALLGQALKWQQHQGLLPP
  GMTIDLFRGKAAVKDVEEEKFPTQLSRHIKFGQKSHVECARFSPDGQYLVTGSVDGFIEV
  WNFTTGKIRKDLKYQAQDNFMMMDDAVLCMCFSRDTEMLATGAQDGKIKVWKIQSGQCLR
  RFERAHSKGVTCLSFSKDSSQILSASFDQTIRIHGLKSGKTLKEFRGHSSFVNEATFTQD
  GHYIISASSDGTVKIWNMKTTECSNTFKSLGSTAGTDITVNSVILLPKNPEHFVVCNRSN
  TVVIMNMQGQIVRSFSSGKREGGDFVCCALSPRGEWIYCVGEDFVLYCFSTVTGKLERTL
  TVHEKDVIGIAHHPHQNLIATYSEDGLLKLWKP
• Function: Involved in pre-mRNA splicing as a component of the spliceosome. Regulates alternative splicing of the HSPG2 pre-mRNA. Required for normal accumulation of IK. Required for normal mitotic spindle assembly and normal progress through mitosis; (Microbial infection) Required, together with IK, for normal splicing of influenza A virus NS1 pre-mRNA, which is required for the production of the exportin NS2 and for the production of influenza A virus particles. Not required for the production of VSV virus particles.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[1]
Influenza	DIS3PNU3	moderate	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of WD40 repeat-containing protein SMU1 (SMU1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of WD40 repeat-containing protein SMU1 (SMU1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of WD40 repeat-containing protein SMU1 (SMU1).	[5]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of WD40 repeat-containing protein SMU1 (SMU1).	[6]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of WD40 repeat-containing protein SMU1 (SMU1).	[7]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of WD40 repeat-containing protein SMU1 (SMU1).	[8]

References

• [1] Chromosome instability caused by mutations in the genes involved in transcription and splicing.RNA Biol. 2019 Nov;16(11):1521-1525. doi: 10.1080/15476286.2019.1652523. Epub 2019 Aug 12.
• [2] Destabilization of the human RED-SMU1 splicing complex as a basis for host-directed antiinfluenza strategy.Proc Natl Acad Sci U S A. 2019 May 28;116(22):10968-10977. doi: 10.1073/pnas.1901214116. Epub 2019 May 10.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [7] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.