Target Information
Target General Infomation | |||||
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Target ID |
T78198
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Former ID |
TTDC00091
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Target Name |
Purine nucleoside phosphorylase
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Gene Name |
PNP
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Synonyms |
Inosine phosphorylase; Purine-nucleoside phosphorylase; PNP
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Target Type |
Clinical Trial
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Disease | Autoimmune diabetes [ICD10: E08-E13] | ||||
Gout; Moderate-to-severe plaque psoriasis [ICD9:274.00274.1274.8274.9, 696; ICD10: M10, L40] | |||||
Refractory cutaneous T-cell lymphoma; B-cell acute lymphoblastic leukemia [ICD9: 202.1, 202.2, 202.8, 204.0, 208.9; ICD10: C81-C86, C84.0, C84.1, C91-C95, C91.0] | |||||
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06] | |||||
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.
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BioChemical Class |
Pentosyltransferase
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Target Validation |
T78198
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UniProt ID | |||||
EC Number |
EC 2.4.2.1
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Sequence |
MENGYTYEDYKNTAEWLLSHTKHRPQVAIICGSGLGGLTDKLTQAQIFDYGEIPNFPRST
VPGHAGRLVFGFLNGRACVMMQGRFHMYEGYPLWKVTFPVRVFHLLGVDTLVVTNAAGGL NPKFEVGDIMLIRDHINLPGFSGQNPLRGPNDERFGDRFPAMSDAYDRTMRQRALSTWKQ MGEQRELQEGTYVMVAGPSFETVAECRVLQKLGADAVGMSTVPEVIVARHCGLRVFGFSL ITNKVIMDYESLEKANHEEVLAAGKQAAQKLEQFVSILMASIPLPDKAS |
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Structure |
1M73; 1PF7; 1PWY; 1RCT; 1RFG; 1RR6; 1RSZ; 1RT9; 1ULA; 1ULB; 1V2H; 1V3Q; 1V41; 1V45; 1YRY; 2A0W; 2A0X; 2A0Y; 2OC4; 2OC9; 2ON6; 2Q7O; 3BGS; 3D1V; 3GB9; 3GGS; 3INY; 3K8O; 3K8Q; 3PHB; 4EAR; 4EB8; 4ECE; 4GKA
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Drugs and Mode of Action | |||||
Drug(s) | 2'3'-Dideoxyinosine | Drug Info | Phase 2 | Discovery agent | [521413] |
BCX-3408 | Drug Info | Phase 2 | Discovery agent | [522068] | |
BCX-4208 | Drug Info | Phase 2 | Gout; Moderate-to-severe plaque psoriasis | [523572] | |
Ulodesine | Drug Info | Phase 2 | Autoimmune diabetes | [523572] | |
Forodesine | Drug Info | Phase 1/2 | Refractory cutaneous T-cell lymphoma; B-cell acute lymphoblastic leukemia | [536739], [543027] | |
Guanosine | Drug Info | Phase 1 | Discovery agent | [467804], [523731] | |
Peldesine | Drug Info | Phase 1 | Discovery agent | [521434] | |
CI-972 | Drug Info | Discontinued in Phase 1 | Rheumatoid arthritis | [545178] | |
Inhibitor | (+/-)-5'-deoxy-4'-fluoro-5'-methylthio-DADMe-ImmH | Drug Info | [529677] | ||
2'3'-Dideoxyinosine | Drug Info | [551393] | |||
2,8-Diamino-9-benzyl-1,9-dihydro-purin-6-one | Drug Info | [534048] | |||
2-Hydroxymethyl-Pyrrolidine-3,4-Diol | Drug Info | [551391] | |||
3-((2-Pyrrolidine-1-yl)-ethyl)uracil | Drug Info | [531149] | |||
3-Deoxyguanosine | Drug Info | [551393] | |||
5'-deoxy-4'-hydroxy-5'-methylthio-DADMe-ImmH | Drug Info | [529677] | |||
5'-Methylthio-ImmH | Drug Info | [529677] | |||
5'-methylthio-immucillin-H | Drug Info | [531149] | |||
5'-phenylthio-ImmH | Drug Info | [529677] | |||
8-amino-5'-deoxy-5'-chloroguanosine | Drug Info | [537731] | |||
8-amino-9-benzylguanine | Drug Info | [537731] | |||
8-AMINOGUANINE | Drug Info | [534048] | |||
8-aminoguanosine | Drug Info | [537760] | |||
8-aza-DADMe-ImmH | Drug Info | [535759] | |||
8-Azaguanine | Drug Info | [551393] | |||
8-Iodo-Guanine | Drug Info | [551393] | |||
9-(5',5'-difluoro-5'-phosphonopentyl)guanine | Drug Info | [530755] | |||
9-(5,5-Difluoro-5-Phosphonopentyl)Guanine | Drug Info | [551393] | |||
9-Deazahypoxanthine | Drug Info | [551393] | |||
9-Deazainosine | Drug Info | [551393] | |||
9-DEAZAINOSINE-2',3'-O-ETHYLIDENEPHOSPHONATE | Drug Info | [551374] | |||
Aza-C-nucleosides | Drug Info | [535761] | |||
BCX-3408 | Drug Info | [529290] | |||
BCX-4208 | Drug Info | [549732] | |||
CI-972 | Drug Info | [536061] | |||
DADMe-ImmG | Drug Info | [535759] | |||
DADMe-ImmH | Drug Info | [535759] | |||
Forodesine | Drug Info | [536974], [537256], [537497] | |||
Guanosine | Drug Info | [551393] | |||
GUANOSINE-2',3'-O-ETHYLIDENEPHOSPHONATE | Drug Info | [551374] | |||
GUANOSINE-2',3'-O-METHYLIDENEPHOSPHONATE | Drug Info | [551374] | |||
Hypoxanthine | Drug Info | [551393] | |||
Immucillin-G | Drug Info | [535761] | |||
MT-Immucillin-H | Drug Info | [551399] | |||
Peldesine | Drug Info | [551393] | |||
Ribose-1-Phosphate | Drug Info | [551393] | |||
Ulodesine | Drug Info | [1572591] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
BioCyc Pathway | Arsenate detoxification I (glutaredoxin) | ||||
Purine nucleotides degradation | |||||
Urate biosynthesis/inosine 5' | |||||
-phosphate degradation | |||||
Purine deoxyribonucleosides degradation | |||||
Purine ribonucleosides degradation to ribose-1-phosphate | |||||
Guanosine nucleotides degradation | |||||
Adenosine nucleotides degradation | |||||
Superpathway of purine nucleotide salvage | |||||
Adenine and adenosine salvage III | |||||
Guanine and guanosine salvage | |||||
KEGG Pathway | Purine metabolism | ||||
Pyrimidine metabolism | |||||
Nicotinate and nicotinamide metabolism | |||||
Metabolic pathways | |||||
NetPath Pathway | TCR Signaling Pathway | ||||
EGFR1 Signaling Pathway | |||||
PANTHER Pathway | Adenine and hypoxanthine salvage pathway | ||||
Xanthine and guanine salvage pathway | |||||
PathWhiz Pathway | Purine Metabolism | ||||
Nicotinate and Nicotinamide Metabolism | |||||
Reactome | Purine salvage | ||||
Purine catabolism | |||||
WikiPathways | miR-targeted genes in squamous cell - TarBase | ||||
miR-targeted genes in lymphocytes - TarBase | |||||
miR-targeted genes in leukocytes - TarBase | |||||
miR-targeted genes in epithelium - TarBase | |||||
Metabolism of nucleotides | |||||
References | |||||
Ref 467804 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4567). | ||||
Ref 521413 | ClinicalTrials.gov (NCT00000657) Comparison of 2',3'-Dideoxyinosine (Didanosine, ddI) and Zidovudine in Therapy of Patients With the AIDS Dementia Complex. U.S. National Institutes of Health. | ||||
Ref 521434 | ClinicalTrials.gov (NCT00002237) A Study of Peldesine (BCX-34) in HIV-Infected Patients. U.S. National Institutes of Health. | ||||
Ref 522068 | ClinicalTrials.gov (NCT00504270) A Study of R3421 in Patients With Moderate to Severe Chronic Plaque Psoriasis.. U.S. National Institutes of Health. | ||||
Ref 523572 | ClinicalTrials.gov (NCT01407874) A Randomized, Double-Blind, Dose-Response Study of the Safety and Uric Acid Effects of Oral Ulodesine Added to Allopurinol in Subjects With Gout and Concomitant Moderate Renal Insufficiency. U.S. National Institutes of Health. | ||||
Ref 523731 | ClinicalTrials.gov (NCT01493570) Assessment of Exposure of BI 409306 in Cerebrospinal Fluid (CSF) Relative to Plasma as Well as to Evaluation of the Effect of Different Doses of BI 409306 on the cGMP(Cyclic Guanosine Monophosphate) Levels in CSF in Healthy Male Volunteers. U.S. National Institutes of Health. | ||||
Ref 536739 | Emerging drugs in cutaneous T cell lymphoma. Expert Opin Emerg Drugs. 2008 Jun;13(2):345-61. | ||||
Ref 529290 | J Med Chem. 2008 Feb 28;51(4):948-56. Epub 2008 Feb 6.Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases. | ||||
Ref 529677 | Bioorg Med Chem Lett. 2008 Nov 15;18(22):5900-3. Epub 2008 Aug 19.Immucillins in custom catalytic-site cavities. | ||||
Ref 530755 | Bioorg Med Chem. 2010 Mar 15;18(6):2275-84. Epub 2010 Feb 4.Structural-based design and synthesis of novel 9-deazaguanine derivatives having a phosphate mimic as multi-substrate analogue inhibitors for mammalian PNPs. | ||||
Ref 531149 | Eur J Med Chem. 2010 Nov;45(11):5140-9. Epub 2010 Aug 14.Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase. | ||||
Ref 534048 | J Med Chem. 1993 Apr 16;36(8):1024-31.Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase. | ||||
Ref 535759 | Achieving the ultimate physiological goal in transition state analogue inhibitors for purine nucleoside phosphorylase. J Biol Chem. 2003 Aug 22;278(34):31465-8. Epub 2003 Jul 3. | ||||
Ref 535761 | Exploring structure-activity relationships of transition state analogues of human purine nucleoside phosphorylase. J Med Chem. 2003 Jul 17;46(15):3412-23. | ||||
Ref 536061 | 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. | ||||
Ref 536974 | Novel therapies for cutaneous T-cell lymphomas. Clin Lymphoma Myeloma. 2008 Dec;8 Suppl 5:S187-92. | ||||
Ref 537256 | Synthesis of analogs of forodesine HCl, a human purine nucleoside phosphorylase inhibitor-Part I. Bioorg Med Chem Lett. 2009 May 15;19(10):2624-6. Epub 2009 Apr 9. | ||||
Ref 537497 | Forodesine has high anti-tumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis via induction of p73 and BIM. Blood. 2009 Jun 18. | ||||
Ref 537731 | 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. | ||||
Ref 537760 | Differential metabolism of guanine nucleosides by human lymphoid cell lines. Proc Soc Exp Biol Med. 1985 Sep;179(4):427-31. | ||||
Ref 549732 | 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. | ||||
Ref 551391 | DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January |
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