Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIS03D)

• DTT Name: Alpha-galactosidase A (GLA)
• Synonyms: Melibiase; INN=Agalsidase; Alpha-D-galactoside galactohydrolase; Alpha-D-galactosidase A
• Gene Name: GLA
• DTT Type: Successful target; [1]
• BioChemical Class: Glycosylase
• UniProt ID: AGAL_HUMAN
• TTD ID: T21678
• EC Number: EC 3.2.1.22
• Sequence:
  MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP
  DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL
  ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL
  ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK
  SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL
  RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEIG
  GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT
  MQMSLKDLL
• Function: A homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. Predominantly hydrolyzes ceramide trihexoside, and can catalyze the hydrolysis of melibiose into galactose and glucose.
• KEGG Pathway:
  Galactose metabolism (hsa00052)
  Glycerolipid metabolism (hsa00561)
  Sphingolipid metabolism (hsa00600)
  Glycosphingolipid biosynthesis - globo series (hsa00603)
  Lysosome (hsa04142)
• Reactome Pathway: Glycosphingolipid metabolism (R-HSA-1660662)
• BioCyc Pathway: MetaCyc:HS02389-MON

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Migalastat	DMFIQ2H	Fabry disease	5C56.01	Approved	[1]
Pegunigalsidase alfa	DMOUW65	Fabry disease	5C56.01	Approved	[2]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4D-310	DMNG59Y	Fabry disease	5C56.01	Phase 1/2	[3]
AVR-RD-01	DMC1XHK	Fabry disease	5C56.01	Phase 1/2	[4]
isaralgagene civaparvovec	DM5SSPZ	Fabry disease	5C56.01	Phase 1/2	[5]
ST-920	DMOJIPG	Fabry disease	5C56.01	Phase 1/2	[6]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+)-5-deoxyadeenophorine	DMF8C50	Discovery agent	N.A.	Investigative	[7]
2,5-dideoxy-2,5-imino-D-altritol	DMI1O54	Discovery agent	N.A.	Investigative	[8]
Alpha-D-Mannose	DMF5DLW	Discovery agent	N.A.	Investigative	[9]
Beta-1-C-butenyl-1-deoxygalactonojirimycin	DM6GTBC	Discovery agent	N.A.	Investigative	[8]
Beta-1-C-Butyl-1-deoxygalactonojirimycin	DMMKDEZ	Discovery agent	N.A.	Investigative	[8]
CALYSTEGINE B2	DMMBA70	Discovery agent	N.A.	Investigative	[10]
Fucose	DMAHMSV	N. A.	N. A.	Investigative	[9]

References

• [1] AT-1001: a high-affinity alpha3beta4 nAChR ligand with novel nicotine-suppressive pharmacology. Br J Pharmacol. 2015 Apr;172(7):1834-45.
• [2] Characterization of a chemically modified plant cell culture expressed human alpha-Galactosidase-A enzyme for treatment of Fabry disease. Mol Genet Metab. 2015 Feb;114(2):259-67.
• [3] Clinical pipeline report, company report or official report of 4D Molecular Therapeutics
• [4] Clinical pipeline report, company report or official report of Avrobio.
• [5] ClinicalTrials.gov (NCT04046224) A Phase I/II, Multicenter, Open-Label, Single-Dose, Dose-Ranging Study to Assess the Safety and Tolerability of ST-920, an AAV2/6 Human Alpha Galactosidase A Gene Therapy, in Subjects With Fabry Disease (STAAR). U.S.National Institutes of Health.
• [6] AAV2/6 Gene Therapy in a Murine Model of Fabry Disease Results in Supraphysiological Enzyme Activity and Effective Substrate Reduction. Mol Ther Methods Clin Dev. 2020 Jul 9;18:607-619.
• [7] Flexible synthesis and biological evaluation of novel 5-deoxyadenophorine analogues. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3262-7.
• [8] 2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease. Bioorg Med Chem. 2010 Jun 1;18(11):3790-4.
• [9] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [10] Identification of the glycosidase inhibitors swainsonine and calystegine B2 in Weir vine (Ipomoea sp. Q6 [aff. calobra]) and correlation with toxicity. J Nat Prod. 1995 Jun;58(6):878-86.