Synthesis and Biological Activity of a Novel Class of Purine Nucleoside Phosphorylase Inhibitors

Morris, Phillip; Elliott, Arthur J.; Walton, Sandra P.; Williams, Carl H.

doi:10.1080/15257770008033016

Cited by 27 publications

(21 citation statements)

References 17 publications

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“…Several agents have been shown to inhibit PNP, 20 and pharmacokinetic studies have demonstrated that more than 95% continuous inhibition of PNP is required to achieve significant reduction in T-cell levels. 21 Acyclovir, a potent inhibitor of herpes simplex virus replication, also inhibits PNP, albeit to a lesser extent.…”

Section: Introductionmentioning

confidence: 99%

“…Enzymatic studies indicated that BCX-34 had a rapid off rate and could not inhibit PNP sufficiently to elevate plasma dGuo to levels necessary for T-cell suppression. 20,28 Schramm's group used another strategy to design more potent PNP inhibitors by identification of the transition-state structure stabilized by the target enzyme. [29][30][31] Geometric and electrostatic properties of the transition state of substrate were used as an atomic blueprint to design chemically stable isologues to act as analogs.…”

Section: Introductionmentioning

confidence: 99%

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A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

Gandhi

Kilpatrick

Plunkett

et al. 2005

Blood

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

Gandhi

Kilpatrick

Plunkett

et al. 2005

Blood

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“…Other analogues related to the first-generation inhibitors have also been reported by Morris et al [23,24]. …”

Section: Chemistry Of First-generation Pnp Inhibitorsmentioning

confidence: 79%

The Design of Forodesine HCl and Other Purine Nucleoside Phosphorylase Inhibitors

Morris

Kamath

2008

Modified Nucleosides

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Purine nucleoside phosphorylase (PNP) is a purine-metabolizing enzyme that catalyzes the reversible phosphorolysis of purine nucleosides such as 2 0 -deoxyguanosine (dGuo) and 2 0 -deoxyinosine to their respective bases and deoxyribose-a-1-phosphate [1][2][3][4][5]. In cells, PNP normally acts in the phosphorolytic direction, since the 6-oxopurine metabolic products are further metabolized. The importance of PNP to the integrity of the immune system became apparent with the description of a rare form of immune deficiency found in children who are genetically deficient in the PNP enzyme [6]. Children lacking the PNP enzyme have severe T-cell immunodeficiency while, in most cases, maintaining normal or high B-cell function. The biochemical mechanism underlying the T-cell selective immunosuppression in PNP-deficient patients has been extensively studied. Metabolically, these patients have a low uric acid concentration as they lack the necessary hypoxanthine or guanine substrates. These patients also have elevated levels of the nucleosides 2 0 -deoxyguanosine, 2 0 -deoxyinosine, inosine and guanosine as they lack the PNP enzyme necessary to catabolize these materials. While all nucleoside levels are elevated, only dGuo affects the T-cell population. As the concentration of dGuo increases within cells, it accumulates and is phosphorylated to 2 0 -deoxyguanosine phosphate (dGMP) by the enzyme 2 0 -deoxycytidine kinase. Subsequently, dGMP is converted to 2 0 -deoxyguanosine diphosphate (dGDP), which is then further converted to the triphosphate (dGTP) [7,8]. The elevated dGTP level creates an imbalance in the endogenous nucleotide pool, which in turn induces apoptosis (Figure 18.1).The unique sensitivity of human T cells to PNP deficiency is attributed to a relatively high level of kinase and a low level of nucleotidase activity compared to other cell types. This unique enzyme ratio is especially characteristic of immature T cells. Based upon these observations, several novel classes of PNP inhibitors have been designed for the treatment of T-cell-mediated diseases. Among the diseases Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn

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“…Further crystallographic studies improved the resolution to 2.8 Å (Ealick et al 1991). These atomic coordinates were extensively used for structure-based design of PNP inhibitors (Woo et al 1992, Chern et al 1993, Guida et al 1994, Morris et al 2000. However, the deposited atomic coordinates of human PNP (PDB access codes: 1ULA and 1ULB) were recently withdrawn due to low resolution.…”

Section: T-cell Immunomodulationmentioning

confidence: 99%

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

Basso

Silva

Fett-Neto

et al. 2005

Mem. Inst. Oswaldo Cruz

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Synthesis and Biological Activity of a Novel Class of Purine Nucleoside Phosphorylase Inhibitors

Cited by 27 publications

References 17 publications

A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

The Design of Forodesine HCl and Other Purine Nucleoside Phosphorylase Inhibitors

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

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