Purine nucleoside phosphorylase: A target for drug design

Montgomery, John A.

doi:10.1002/med.2610130302

Cited by 77 publications

(102 citation statements)

References 29 publications

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“…The PNP enzyme family is an im portant target for drug design (Stoeckler, 1984;Montgomery, 1993). Potent inhibitors of mammalian phospho rylases may be useful in many circumstances, e.g.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 6-Aryloxy- and 6-Arylalkoxy-2-chloropurines and Their Interactions with Purine Nucleoside Phosphorylase from Escherichia coli

Bzowska

Magnowska

Kazimierczuk³

1999

Zeitschrift Für Naturforschung C

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The phase transfer method was applied to perform the nucleophilic substitution of 2,6-dichloropurines by modified arylalkyl alcohol or phenols. Since under these conditions only the 6-halogen is exchanged, this method gives 2-chloro-6-aryloxy-and 2-chloro-6-arylalkoxypurines. 2-Chloro-6-benzylthiopurine was synthesized by alkylation of 2-chloro-6-thiopurine with benzyl bromide. The stereoisom ers of 2-chloro-6-(l-phenyl-l-ethoxy)purine were ob tained from R-and 5-enantiomers of sec.-phenylethylalcohol and 2,6-dichloropurine.A ll derivatives were tested for inhibition with purified hexameric E. coli purine nucleoside phosphorylase (PNP). For analogues showing IC50 < 10 ^.m, the type o f inhibition and inhibi tion constants were determined. In all cases the experimental data were best described by the mixed-type inhibition model and the uncompetitive inhibition constant, Kiu, was found to be several-fold lower than the competitive inhibition constant, Kic. This effect seems to be due to the 6-aryloxy-or 6-arylalkoxy substituent, because a natural PNP substrate adenine, as well as 2-chloroadenine, show mixed type inhibition with almost the same inhibition con stants Kiu and K1C . = 0.4, 0.6, 1.4, 1.4 and 2.2 [im, respectively). The i?-stereoisomer o f 2-chloro-6-(lpheny-l-ethoxy)purine has Kiu = 2.0 ^im, whereas inhibition o f its S counterpart is rather weak (IC50> 12 jim). More rigid (e.g. phenoxy-), non-planar (cyclohexyloxy-), or more bulky (2,4,6-trimethylphenoxy-) substituents at position 6 of the purine base gave less potent inhibi tors (IC50 = 26, 56 and >100 [im, respectively). The derivatives are selective inhibitors of hexameric "high-molecular mass" PNPs because no inhibitory activity vs. trimeric Cellulomonas sp. PNP was detected. The most potent inhibition was observed for 6-benzylthio-2-chloro-, 6-benzyloxy-2-chloro-, 2-chloro-6-(2-phenyl-l-ethoxy), 2-chloro-6-(3-phenyl-l-propoxy)-and 2-chloro-6-ethoxypurines (KiuBy establishing the ligand-dependent stabilization pattern of the E. coli PNP it was shown that the new derivatives, similarly as the natural purine bases, are able to form a dead-end ternary complex with the enzyme and orthophosphate. It was also shown that the derivatives are substrates in the reverse synthetic direction catalyzed by E. coli PNP

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“…The PNP enzyme family is an im portant target for drug design (Stoeckler, 1984;Montgomery, 1993). Potent inhibitors of mammalian phospho rylases may be useful in many circumstances, e.g.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 6-Aryloxy- and 6-Arylalkoxy-2-chloropurines and Their Interactions with Purine Nucleoside Phosphorylase from Escherichia coli

Bzowska

Magnowska

Kazimierczuk³

1999

Zeitschrift Für Naturforschung C

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“…This confirms previous studies showing that 9-deazaguanine analogs are more potent than the corresponding guanine analogs. 6,28,29 A hypoxanthine analog of the data set (compound 4, IC 50 = 17 μM), which is structurally related to compounds 2 and 3, is 12-fold less potent than compound 3, and about 2-fold more potent than the guanine analog 2. These results highlight the importance of the 9-deazaguanine scaffold in the development of selective inhibitors of SmPNP, indicating that stereochemical features in the ribose binding site might play a pivotal role in SmPNP inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…4,5 Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is a key enzyme in the purine salvage pathway which has been primarily studied as a target for the treatment of T-cell proliferative diseases, such as T-cell leukemias or lymphomas, organ transplant rejection, rheumatoid arthritis, psoriasis, and some other autoimmune diseases. 6,7 In fact, two inhibitors discovered at BioCryst Pharmaceuticals are currently undergoing clinical trials: (i) BCX1777 (forodesine) for the treatment of cutaneous T-cell lymphoma, chronic lymphocytic leukemia and acute lymphoblastic leukemia; and (ii) BCX4208 for the treatment of gout. 8 More recently, it has been suggested that PNP inhibitors could also be used for the therapy of parasitic tropical diseases, such as malaria and schistosomiasis.…”

Section: Introductionmentioning

confidence: 99%

Enzyme kinetics, structural analysis and molecular modeling studies on a series of Schistosoma mansoni PNP inhibitors

Postigo¹,

Krogh²,

Terni³

et al. 2011

J. Braz. Chem. Soc.

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A enzima purina nucleosídeo fosforilase do parasita Schistosoma mansoni (SmPNP) é um alvo molecular atrativo para o desenvolvimento de candidatos a novos fármacos para o tratamento da esquistossomose, doença tropical negligenciada que afeta mais de 200 milhões de pessoas em todo mundo. No presente trabalho, estudos de cinética enzimática foram conduzidos para a determinação da potência e do mecanismo de inibição de uma série de inibidores da enzima SmPNP. Além das investigações bioquímicas, estudos cristalográficos e de modelagem molecular revelaram importantes bases moleculares para a afinidade de ligação frente à enzima alvo, levando ao desenvolvimento de relações entre a estrutura e atividade (SAR).The enzyme purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive molecular target for the development of novel drugs against schistosomiasis, a neglected tropical disease that affects about 200 million people worldwide. In the present work, enzyme kinetic studies were carried out in order to determine the potency and mechanism of inhibition of a series of SmPNP inhibitors. In addition to the biochemical investigations, crystallographic and molecular modeling studies revealed important molecular features for binding affinity towards the target enzyme, leading to the development of structure-activity relationships (SAR).

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“…Purine nucleoside phosphorylase (PNP, E.C.2.4.2.1) catalyzes the reversible cleavage of the glycosidic bond of natural riboand 2 -deoxyribonucleosides, generating the corresponding base and ribose (deoxyribose)-1-phosphate (Bzowska et al, 2000;Montgomery, 1993). Interest in PNP arises from its key role in the purine salvage pathway that enables the cells to utilize purine bases to synthesize purine nucleotides, and from its role in T-cell development (Bzowska et al, 2000;Deng et al, 2006;Montgomery, 1993;Pui and Jeha, 2007;Silva et al, 2007).…”

Section: Introductionmentioning

confidence: 99%