Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTLPC70)

• DTT Name: Lysosomal alpha-glucosidase (GAA)
• Synonyms: GAA; Aglucosidase alfa; Acid maltase
• Gene Name: GAA
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Glycosylase
• UniProt ID: LYAG_HUMAN
• TTD ID: T31514
• EC Number: EC 3.2.1.20
• Sequence:
  MGVRHPPCSHRLLAVCALVSLATAALLGHILLHDFLLVPRELSGSSPVLEETHPAHQQGA
  SRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGA
  QMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLH
  FTIKDPANRRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVLLNTTVAPLF
  FADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLA
  LEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGY
  PFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDG
  FRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKV
  WPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELEN
  PPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPFVISR
  STFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVR
  WTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAG
  ETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPV
  EALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQP
  MALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQ
  LQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC
• Function: Essential for the degradation of glygogen to glucose in lysosomes.
• KEGG Pathway:
  Galactose metabolism (hsa00052)
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Glycogen breakdown (glycogenolysis) (R-HSA-70221)
  Glycogen storage disease type II (GAA) (R-HSA-5357609)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Avalglucosidase alfa	DMPW5UF	Pompe disease	5C51.3	Approved	[2]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMN-701	DM94Y6O	Pompe disease	5C51.3	Phase 3	[1]
Deoxynojirimycin	DM2ATZB	Pompe disease	5C51.3	Phase 3	[3]
AT845	DMZJIIB	Pompe disease	5C51.3	Phase 2	[4]
SALACINOL	DMVKQT8	N. A.	N. A.	Phase 1/2	[5]
SPK-3006	DMK9DG5	Pompe disease	5C51.3	Phase 1/2	[6]
GZ402666	DMGO6M1	Pompe disease	5C51.3	Phase 1	[7]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
5-(4-(4-Acetylphenyl)piperazin-1-ylsulfonyl)-6-chloroindolin-2-one	DMAJWLD	Pompe disease	5C51.3	Preclinical	[8]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(-)-uniflorine A	DMRGVNJ	Discovery agent	N.A.	Investigative	[9]
(R)-2,6-Bis-hydroxymethyl-piperidine-3,4,5-triol	DMRO9C7	Discovery agent	N.A.	Investigative	[10]
2,5-imino-2,5,6-trideoxy-D-manno-heptitol	DM5IJSW	Discovery agent	N.A.	Investigative	[11]
7-O-b-D-Glucopyranosyl-a-homonojirimycin	DM8IY3D	Discovery agent	N.A.	Investigative	[3]
Alpha-7-Deoxyhomonojirimycin	DMND5EU	Discovery agent	N.A.	Investigative	[12]
Alpha-Homonojirimycin	DMT17H0	Discovery agent	N.A.	Investigative	[3]
N-adamantanemethyloxypentyl-1-deoxynojirimycin	DMSR4A6	Discovery agent	N.A.	Investigative	[13]
UNIFLORINE B	DMFH79T	Discovery agent	N.A.	Investigative	[9]
VALIOLAMINE	DM2VQN5	Discovery agent	N.A.	Investigative	[3]

References

• [1] Clinical pipeline report, company report or official report of BioMarin Pharma.
• [2] ClinicalTrials.gov (NCT02782741) Study to Compare the Efficacy and Safety of Enzyme Replacement Therapies Avalglucosidase Alfa and Alglucosidase Alfa Administered Every Other Week in Patients With Late-onset Pompe Disease Who Have Not Been Previously Treated for Pompe Disease (COMET). U.S. National Institutes of Health.
• [3] In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures. Bioorg Med Chem. 2008 Aug 1;16(15):7330-6.
• [4] Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. EMBO Mol Med. 2022 Jan 11;14(1):e13968.
• [5] Alpha-glucosidase inhibitor from Kothala-himbutu (Salacia reticulata WIGHT). J Nat Prod. 2008 Jun;71(6):981-4.
• [6] Clinical pipeline report, company report or official report of Spark Therapeutics
• [7] ClinicalTrials.gov (NCT01898364) Safety and Efficacy Evaluation of Repeat neoGAA Dosing in Late Onset Pompe Disease Patients.. U.S. National Institutes of Health.
• [8] 5-(4-(4-Acetylphenyl)piperazin-1-ylsulfonyl)indolin-2-one Analogs as Inhibitors of Acid alpha-Glucosidase for Potential Chaperone Treatment of Pompe Disease or Intervention for Diabetes Mellitus Type 2. N.A.. N.A.
• [9] Total synthesis of (-)-uniflorine A. J Nat Prod. 2009 Nov;72(11):2058-60.
• [10] Homonojirimycin isomers and N-alkylated homonojirimycins: structural and conformational basis of inhibition of glycosidases. J Med Chem. 1998 Jul 2;41(14):2565-71.
• [11] Nitrogen-containing furanose and pyranose analogues from Hyacinthus orientalis. J Nat Prod. 1998 May;61(5):625-8.
• [12] New polyhydroxylated pyrrolidine, piperidine, and pyrrolizidine alkaloids from Scilla sibirica. J Nat Prod. 2002 Dec;65(12):1875-81.
• [13] Synthesis and evaluation of D-gluco-pyranocyclopropyl amines as potential glucosidase inhibitors. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6600-3.