Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTMCF1Y)

• DTT Name: Purine nucleoside phosphorylase (PNP)
• Synonyms: PNP; Inosine phosphorylase
• Gene Name: PNP
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Pentosyltransferase
• UniProt ID: PNPH_HUMAN
• TTD ID: T78198
• EC Number: EC 2.4.2.1
• Sequence:
  MENGYTYEDYKNTAEWLLSHTKHRPQVAIICGSGLGGLTDKLTQAQIFDYGEIPNFPRST
  VPGHAGRLVFGFLNGRACVMMQGRFHMYEGYPLWKVTFPVRVFHLLGVDTLVVTNAAGGL
  NPKFEVGDIMLIRDHINLPGFSGQNPLRGPNDERFGDRFPAMSDAYDRTMRQRALSTWKQ
  MGEQRELQEGTYVMVAGPSFETVAECRVLQKLGADAVGMSTVPEVIVARHCGLRVFGFSL
  ITNKVIMDYESLEKANHEEVLAAGKQAAQKLEQFVSILMASIPLPDKAS
• Function: The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta- (deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Nicotinate and nicotinamide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Purine catabolism (R-HSA-74259)
  Purine salvage (R-HSA-74217)
• BioCyc Pathway: MetaCyc:HS02151-MON

Molecular Interaction Atlas (MIA) of This DTT

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2'3'-Dideoxyinosine	DMZWNQF	N. A.	N. A.	Phase 2	[2]
BCX-3408	DMRSG31	Autoimmune diabetes	5A10	Phase 2	[1]
Forodesine	DME2W4T	B-cell acute lymphoblastic leukaemia	2B33.3	Phase 1/2	[3]
Guanosine	DM4T5LH	N. A.	N. A.	Phase 1	[2]
Peldesine	DMHV58T	N. A.	N. A.	Phase 1	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CI-972	DM9ZBO0	Rheumatoid arthritis	FA20	Discontinued in Phase 1	[4]

27 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)-5'-deoxy-4'-fluoro-5'-methylthio-DADMe-ImmH	DMQP5U9	Discovery agent	N.A.	Investigative	[5]
2-Hydroxymethyl-Pyrrolidine-3,4-Diol	DM7MUZ1	Discovery agent	N.A.	Investigative	[6]
3-((2-Pyrrolidine-1-yl)-ethyl)uracil	DMSGX7V	Discovery agent	N.A.	Investigative	[7]
3-Deoxyguanosine	DMFQUGE	Discovery agent	N.A.	Investigative	[2]
5'-deoxy-4'-hydroxy-5'-methylthio-DADMe-ImmH	DMRFH9U	Discovery agent	N.A.	Investigative	[5]
5'-Methylthio-ImmH	DM3LY0Q	Discovery agent	N.A.	Investigative	[5]
5'-methylthio-immucillin-H	DMK52UH	Discovery agent	N.A.	Investigative	[7]
5'-phenylthio-ImmH	DMQMZ0Y	Discovery agent	N.A.	Investigative	[5]
7-tert-butyl-2, 3-dihydro-3, 3-dimethyl substituted dihydrofuran 30 (DHDMBF30)	DMSU06X	Discovery agent	N.A.	Investigative	[8]
8-amino-9-benzylguanine	DMSNG7M	N. A.	N. A.	Investigative	[8]
8-AMINOGUANINE	DMYXJG7	Discovery agent	N.A.	Investigative	[9]
8-aminoguanosine	DM0JEA6	Discovery agent	N.A.	Investigative	[10]
8-aza-DADMe-ImmH	DMBVFKR	Discovery agent	N.A.	Investigative	[11]
8-Azaguanine	DM7VP90	Discovery agent	N.A.	Investigative	[2]
8-Iodo-Guanine	DM3K1EO	Discovery agent	N.A.	Investigative	[2]
9-(5,5-Difluoro-5-Phosphonopentyl)Guanine	DMGFQLE	Discovery agent	N.A.	Investigative	[2]
9-Deazahypoxanthine	DM3G6LY	Discovery agent	N.A.	Investigative	[2]
9-Deazainosine	DME7ONQ	Discovery agent	N.A.	Investigative	[2]
9-DEAZAINOSINE-2',3'-O-ETHYLIDENEPHOSPHONATE	DM9BCDT	Discovery agent	N.A.	Investigative	[12]
Aza-C-nucleosides	DMOSI4U	Discovery agent	N.A.	Investigative	[13]
DADMe-ImmG	DMJIFY3	Discovery agent	N.A.	Investigative	[11]
GUANOSINE-2',3'-O-ETHYLIDENEPHOSPHONATE	DMCN56S	Discovery agent	N.A.	Investigative	[12]
GUANOSINE-2',3'-O-METHYLIDENEPHOSPHONATE	DMRITFU	Discovery agent	N.A.	Investigative	[12]
Hypoxanthine	DMLSABI	Discovery agent	N.A.	Investigative	[2]
Immucillin-G	DMX2NKO	Discovery agent	N.A.	Investigative	[13]
MT-Immucillin-H	DMK2FOX	Discovery agent	N.A.	Investigative	[14]
Ribose-1-Phosphate	DM7V8DZ	Discovery agent	N.A.	Investigative	[2]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	3.50E-25	1.43	2.13
Rheumatoid arthritis	FA20	Synovial tissue	3.67E-04	1.95	2.55

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Purine nucleoside phosphorylase (PNP) DME Info
• Gene Name: PNP

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ribavirin	DMEYLH9	Hepatitis C virus infection	1E51.1	Approved	[15]

References

• [1] BCX-4208 (RO5092888), a Purine Nucleoside Phosphorylase (PNP) Inhibitor, Is a Novel, Potent Orally Active Anti-T-Cell and B-Cell Agent. 50th ASH Annual Meeting and Exposition. 2008.
• [2] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [3] Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 an... Blood. 2009 Aug 20;114(8):1563-75.
• [4] Inhibitors of human purine nucleoside phosphorylase. Synthesis of pyrrolo[3,2-d]pyrimidines, a new class of purine nucleoside phosphorylase inhibitors as potentially T-cell selective immunosuppressive agents. Description of 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d] pyrimidin-4-one. J Med Chem. 1992 May 1;35(9):1605-9.
• [5] Immucillins in custom catalytic-site cavities. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5900-3.
• [6] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [7] Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase. Eur J Med Chem. 2010 Nov;45(11):5140-9.
• [8] Expression of human malaria parasite purine nucleoside phosphorylase in host enzyme-deficient erythrocyte culture. Enzyme characterization and identification of novel inhibitors. J Biol Chem. 1986 Sep 5;261(25):11667-73.
• [9] Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase. J Med Chem. 1993 Apr 16;36(8):1024-31.
• [10] Differential metabolism of guanine nucleosides by human lymphoid cell lines. Proc Soc Exp Biol Med. 1985 Sep;179(4):427-31.
• [11] Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase. J Biol Chem. 2003 Aug 22;278(34):31465-8.
• [12] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [13] Exploring structure-activity relationships of transition state analogues of human purine nucleoside phosphorylase. J Med Chem. 2003 Jul 17;46(15):3412-23.
• [14] Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function. J Biol Chem. 2004 Apr 30;279(18):18103-6.
• [15] Functional analysis of purine nucleoside phosphorylase as a key enzyme in ribavirin metabolism. Drug Metab Pharmacokinet. 2014;29(2):211-4.