Online citations, reference lists, and bibliographies.
← Back to Search

Immucillin H, A Powerful Transition-state Analog Inhibitor Of Purine Nucleoside Phosphorylase, Selectively Inhibits Human T Lymphocytes

G. Kicska, L. Long, H. Hörig, C. Fairchild, P. Tyler, R. Furneaux, V. Schramm, H. L. Kaufman
Published 2001 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
Transition-state theory has led to the design of Immucillin-H (Imm-H), a picomolar inhibitor of purine nucleoside phosphorylase (PNP). In humans, PNP is the only route for degradation of deoxyguanosine, and genetic deficiency of this enzyme leads to profound T cell-mediated immunosuppression. This study reports the biological effects and mechanism of action of Imm-H on malignant T cell lines and on normal activated human peripheral T cells. Imm-H inhibits the growth of malignant T cell leukemia lines with the induction of apoptosis. Imm-H also inhibits activated normal human T cells after antigenic stimulation in vitro. However, Imm-H did not inhibit malignant B cells, colon cancer cell lines, or normal human nonstimulated T cells, demonstrating the selective activity of Imm-H. The effects on leukemia cells were mediated by the cellular phosphorylation of deoxyguanosine and the accumulation of dGTP, an inhibitor of ribonucleotide diphosphate reductase. Cells were protected from the toxic effects of Imm-H when deoxyguanosine was absent or when deoxycytidine was present. Guanosine incorporation into nucleic acids was selectively blocked by Imm-H with no effect on guanine, adenine, adenosine, or deoxycytidine incorporation. Imm-H may have clinical potential for treatment of human T cell leukemia and lymphoma and for other diseases characterized by abnormal activation of T lymphocytes. The design of Imm-H from an enzymatic transition-state analysis exemplifies a powerful approach for developing high-affinity enzyme inhibitors with pharmacologic activity.
This paper references
10.1152/AJPCELL.1982.243.5.C270
Regulation of purine metabolism by plasma membrane and cytoplasmic 5'-nucleotidases.
N. Edwards (1982)
10.1111/j.1749-6632.1985.tb27093.x
Roles of Alternative Synthetic and Catabolic Purine Pathways in T Lymphocyte Differentiation a
A. Cohen (1985)
10.1097/00007890-200004150-00022
Immune reconstitution after allogeneic bone marrow transplantation depleted of T cells.
G. Davison (2000)
10.1021/BI00004A008
Pre-steady-state transition-state analysis of the hydrolytic reaction catalyzed by purine nucleoside phosphorylase.
P. Kline (1995)
10.1073/PNAS.88.4.1531
Cloning and expression of human deoxycytidine kinase cDNA.
E. Chottiner (1991)
10.1073/PNAS.88.24.11540
Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors.
S. Ealick (1991)
10.1073/PNAS.76.3.1074
Isolation and characterization of purine-nucleoside phosphorylase-deficient T-lymphoma cells and secondary mutants with altered ribonucleotide reductase: genetic model for immunodeficiency disease.
B. Ullman (1979)
10.1016/s0021-9258(19)69266-5
Methotrexate resistance in al L1210 cell line resulting from increased dihydrofolate reductase, decreased thymidylate synthetase activity, and normal membrane transport. Computer simulations based on network thermodynamics.
J. C. White (1981)
Transplantation 69, 1341–1347
G. M. Davison (2000)
10.1021/BI00211A033
Purine nucleoside phosphorylase. Catalytic mechanism and transition-state analysis of the arsenolysis reaction.
P. Kline (1993)
10.1021/BI980658D
One-third-the-sites transition-state inhibitors for purine nucleoside phosphorylase.
R. W. Miles (1998)
10.1172/JCI109639
Erythrocyte metabolism in purine nucleoside phosphorylase deficiency after enzyme replacement therapy by infusion of erythrocytes.
G. E. Staal (1980)
10.1056/NEJM197703242961203
Purine nucleoside phosphorylase deficiency associated with selective cellular immunodeficiency.
J. Stoop (1977)
10.1016/0065-2571(86)90005-1
Protein properties of the subunits of ribonucleotide reductase and the specificity of the allosteric site(s).
J. Cory (1986)
10.1517/13543776.8.3.283
Inhibitors of the enzyme purine nucleoside phosphorylase
P. Morris (1998)
10.1016/0162-3109(96)00123-3
In vivo and in vitro pharmacologic activity of the purine nucleoside phosphorylase inhibitor BCX-34: the role of GTP and dGTP.
S. Bantia (1996)
10.1182/BLOOD.V81.3.597.BLOODJOURNAL813597
Relationship of deoxycytidine kinase and cytoplasmic 5'-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine
H. Kawasaki (1993)
10.1016/S0952-7915(98)80084-8
Control of immune pathology by regulatory T cells.
D. Mason (1998)
10.1016/S0040-4020(00)00194-0
Synthesis of transition state analogue inhibitors for purine nucleoside phosphorylase and N-riboside hydrolases
G. B. Evans (2000)
10.1021/AR50049A002
Analog approaches to the structure of the transition state in enzyme reactions
R. Wolfenden (1972)
10.7326/0003-4819-114-9-816_3
The Metabolic basis of inherited disease
Charles R.scriver (1989)
10.1111/J.1699-0463.1980.TB00110.X
Common variable immunodeficiency and purine nucleotidase and nucleoside phosphorylase deficiency. A case report.
P. A. Ostergaard (1980)
10.1042/BJ2140711
The metabolism of deoxyguanosine and guanosine in human B and T lymphoblasts. A role for deoxyguanosine kinase activity in the selective T-cell defect associated with purine nucleoside phosphorylase deficiency.
W. Osborne (1983)
10.1073/PNAS.75.10.5011
Purinogenic immunodeficiency diseases: selective toxicity of deoxyribonucleosides for T cells.
B. Mitchell (1978)
10.2210/PDB2PNP/PDB
Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution.
S. Ealick (1990)
10.1146/ANNUREV.BIOCHEM.67.1.693
Enzymatic transition states and transition state analog design.
V. Schramm (1998)



This paper is referenced by
10.1021/ja908908q
Analysis of the reaction coordinate of alpha-L-fucosidases: a combined structural and quantum mechanical approach.
Alicia Lammerts van Bueren (2010)
10.1071/CH04112
The Synthesis of N-Ribosyl Transferase Inhibitors Based on a Transition State Blueprint
G. B. Evans (2004)
10.1021/acscentsci.7b00211
Allosteric Communication Networks in Proteins Revealed through Pocket Crosstalk Analysis
Giuseppina La Sala (2017)
10.1182/blood-2009-02-207654
Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM.
R. Alonso (2009)
10.1097/00000441-200312000-00005
Celebrating the SSCI: the drug discovery pathway: challenges and pitfalls.
J. Bennett (2003)
10.1016/j.jaad.2010.08.037
Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC).
E. Olsen (2011)
47th Annual Meeting of the American Society of Hematology Atlanta, GA.
T-Cell Lymphoma (2006)
10.1016/j.bone.2012.09.026
The transition state analog inhibitor of Purine Nucleoside Phosphorylase (PNP) Immucillin-H arrests bone loss in rat periodontal disease models.
C. Deves (2013)
10.1016/j.yexcr.2010.06.023
Activation of guanine-β-D-arabinofuranoside and deoxyguanosine to triphosphates by a common pathway blocks T lymphoblasts at different checkpoints.
Luigi Leanza (2010)
10.1074/jbc.M801572200
Metabolic Interrelations within Guanine Deoxynucleotide Pools for Mitochondrial and Nuclear DNA Maintenance*
Luigi Leanza (2008)
10.2174/18763960010030100179
Cordyceps Mushroom: A Potent Anticancer Nutraceutical
Md. Asaduzzaman Khan (2010)
10.1002/EJOC.201201436
Straightforward Microwave‐Assisted Synthesis of 5,8‐Disubstituted 5,6,8,9‐Te­trahydro‐4H,7H‐2,5,6a,8,9a‐pentaazaphenalene‐1,3‐diones
Daniel Garcia (2013)
10.1182/blood-2011-02-337840
In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia.
I. Homminga (2011)
10.4137/CMO.S7262
Emerging Pharmacotherapies for Adult Patients with Acute Lymphoblastic Leukemia
L. Lee (2012)
10.1038/onc.2008.316
Nucleoside analogs: molecular mechanisms signaling cell death
B. Ewald (2008)
10.1016/j.clml.2013.04.009
Preclinical and clinical evaluation of forodesine in pediatric and adult B-cell acute lymphoblastic leukemia.
K. Balakrishnan (2013)
10.1021/ACS.JMEDCHEM.5B01157
C-Nucleosides To Be Revisited.
E. Clercq (2016)
10.1039/c9cc06975e
PMP–diketopiperazine adducts form at the active site of a PLP dependent enzyme involved in formycin biosynthesis† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc06975e
Sisi Gao (2019)
10.1007/978-1-62703-408-1_19
Cutaneous T-Cell Lymphomas: Mycosis Fungoides and Sézary Syndrome
M. Duvic (2013)
10.4155/fmc.11.117
Iminosugars as therapeutic agents: recent advances and promising trends.
R. Nash (2011)
10.1016/S0003-4509(07)90013-9
Les Iminosucres : applications thérapeutiques actuelles et futures
O. Martin (2007)
10.1182/blood-2009-10-246199
Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells.
K. Balakrishnan (2010)
10.1007/s00277-018-3418-2
Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma
D. Maruyama (2018)
10.1002/chem.201804285
Synthesis of Ribo-Azanucleosides by Anodic Oxidation: Reactivity Control of Intermediate for Efficient Access to Pharmacophores.
K. Okamoto (2018)
10.1074/jbc.M115.675082
The Deoxynucleoside Triphosphate Triphosphohydrolase Activity of SAMHD1 Protein Contributes to the Mitochondrial DNA Depletion Associated with Genetic Deficiency of Deoxyguanosine Kinase*
Elisa Franzolin (2015)
10.1021/jp3109013
PNP diminishes guanosine glycosidic bond strength through restrictive ring pucker as a precursor to phosphorylation.
Christopher B. Barnett (2013)
10.1074/jbc.M505033200
Energetic Mapping of Transition State Analogue Interactions with Human and Plasmodium falciparum Purine Nucleoside Phosphorylases*♦
A. Lewandowicz (2005)
10.1007/978-1-60761-384-8_25
Treatment of Cutaneous T-cell Lymphomas
K. M. Cox (2010)
10.1016/B978-0-444-52824-7.00002-0
Chapter 2 – Antimetabolites
C. Avendaño (2008)
10.1039/b915870g
Glycosidase inhibition: assessing mimicry of the transition state
T. Gloster (2010)
10.1101/810093
Defective Nucleotide Catabolism Defines a Subset of Cancers Sensitive to Purine Nucleoside Phosphorylase Inhibition
Evan R. Abt (2019)
10.1007/978-1-4419-8459-3
New Agents for the Treatment of Acute Lymphblastic Leukemia
V. Saha (2011)
See more
Semantic Scholar Logo Some data provided by SemanticScholar