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Evaluation Of Nucleoside Hydrolase Inhibitors For Treatment Of African Trypanosomiasis

M. Berg, L. Kohl, P. Van der Veken, J. Joossens, M. I. Al-Salabi, V. Castagna, F. Giannese, P. Cos, W. Versées, J. Steyaert, P. Grellier, A. Haemers, M. Degano, L. Maes, H. P. de Koning, K. Augustyns
Published 2010 · Biology, Medicine

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ABSTRACT In this paper, we present the biochemical and biological evaluation of N-arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. Previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of Trypanosoma vivax inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the compounds were tested against bloodstream-form Trypanosoma brucei brucei, only one inhibitor, N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (UAMC-00363), displayed significant activity (mean 50% inhibitory concentration [IC50] ± standard error, 0.49 ± 0.31 μM). Validation in an in vivo model of African trypanosomiasis showed promising results for this compound. Several experiments were performed to investigate why only UAMC-00363 showed antiparasitic activity. First, the compound library was screened against T. b. brucei IAG-NH and inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the previously demonstrated inhibitory effects of the compounds on T. vivax IAG-NH. Second, to verify the uptake of these compounds by T. b. brucei, their affinities for the nucleoside P1 and nucleoside/nucleobase P2 transporters of T. b. brucei were tested. Only UAMC-00363 displayed significant affinity for the P2 transporter. It was also shown that UAMC-00363 is concentrated in the cell via at least one additional transporter, since P2 knockout mutants of T. b. brucei displayed no resistance to the compound. Consequently, no cross-resistance to the diamidine or the melaminophenyl arsenical classes of trypanocides is expected. Third, three enzymes of the purine salvage pathway of procyclic T. b. brucei (IAG-NH, IG-NH, and methylthioadenosine phosphorylase [MTAP]) were investigated using RNA interference. The findings from all these studies showed that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of T. b. brucei and that, therefore, it is possible that UAMC-00363 acts on an additional target.
This paper references
Characterisation of a nucleoside/proton symporter in procyclic Trypanosoma brucei
H. P. de Koning (1998)
10.1074/JBC.271.36.21713
Purine-specific Nucleoside N-Ribohydrolase from Trypanosoma brucei brucei
D. W. Parkin (1996)
10.1074/JBC.M202835200
Different Substrate Recognition Motifs of Human and Trypanosome Nucleobase Transporters
Lynsey J. M. Wallace (2002)
New insights into the mechanism of nucleoside hydrolases from the crystal structure of the Escherichia coli YbeK protein bound to the reaction
L. Muzzolini (2006)
10.1074/JBC.M202319200
Six Related Nucleoside/Nucleobase Transporters fromTrypanosoma brucei Exhibit Distinct Biochemical Functions*
M. Sanchez (2002)
10.1016/s0163-7258(03)00071-8
Potential chemotherapeutic targets in the purine metabolism of parasites.
M. H. El Kouni (2003)
10.1016/S0020-7519(96)00150-6
Molecular and biochemical studies on the hypoxanthine-guanine phosphoribosyltransferases of the pathogenic haemoflagellates.
B. Ullman (1997)
10.1016/j.molbiopara.2008.09.011
Two novel nucleobase/pentamidine transporters from Trypanosoma brucei.
D. Ortiz (2009)
10.1021/BI0511991
New insights into the mechanism of nucleoside hydrolases from the crystal structure of the Escherichia coli YbeK protein bound to the reaction product.
Laura Muzzolini (2006)
10.1016/J.FEMSRE.2005.03.004
Purine and pyrimidine transport in pathogenic protozoa: from biology to therapy.
H. D. de Koning (2005)
10.1021/JM030305Z
Synthesis of second-generation transition state analogues of human purine nucleoside phosphorylase.
G. B. Evans (2003)
10.1016/J.JEP.2006.04.003
Anti-infective potential of natural products: how to develop a stronger in vitro 'proof-of-concept'.
P. Cos (2006)
10.1016/J.DRUP.2007.02.004
Drugs and drug resistance in African trypanosomiasis.
V. Delespaux (2007)
10.1128/EC.2.5.1003-1008.2003
Mechanisms of Arsenical and Diamidine Uptake and Resistance in Trypanosoma brucei
E. Matovu (2003)
10.1083/jcb.200903139
Kinesin 9 family members perform separate functions in the trypanosome flagellum
R. Demonchy (2009)
10.1016/S0065-308X(06)63002-9
Targeting of toxic compounds to the trypanosome's interior.
M. Barrett (2006)
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)
10.1128/AAC.48.5.1515-1519.2004
The Trypanocide Diminazene Aceturate Is Accumulated Predominantly through the TbAT1 Purine Transporter: Additional Insights on Diamidine Resistance in African Trypanosomes
H. D. de Koning (2004)
10.1016/j.bbapap.2009.02.011
Crystal structures of T. vivax nucleoside hydrolase in complex with new potent and specific inhibitors.
W. Versées (2009)
10.1016/j.bmc.2009.01.058
Targeted delivery of compounds to Trypanosoma brucei using the melamine motif.
C. Chollet (2009)
10.1126/SCIENCE.1112642
The Genome of the African Trypanosome Trypanosoma brucei
M. Berriman (2005)
10.1038/361173A0
Arsenical-resistant trypanosomes lack an unusual adenosine transporter
N. Carter (1993)
10.1128/AAC.00425-07
2,N6-Disubstituted Adenosine Analogs with Antitrypanosomal and Antimalarial Activities
B. Rodenko (2007)
10.1002/cmdc.200800231
Synthesis of Bicyclic N‐Arylmethyl‐Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase Inhibitors
M. Berg (2009)
10.1016/J.JMB.2006.03.026
Transition-state complex of the purine-specific nucleoside hydrolase of T. vivax: enzyme conformational changes and implications for catalysis.
W. Versées (2006)
10.1371/journal.pone.0000437
Basal Body Positioning Is Controlled by Flagellum Formation in Trypanosoma brucei
Sabrina Absalon (2007)
10.1016/0006-2952(73)90196-2
Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.
Y. Cheng (1973)
Molecular cloning and expression of a purine specific N-ribohydrolase from trypanosoma bruce1 brvcel
R. Pelle (1997)
10.1074/JBC.M008405200
Inhibition of Trypanosoma brucei Gene Expression by RNA Interference Using an Integratable Vector with Opposing T7 Promoters*
Z. Wang (2000)
10.1016/S0166-6851(97)00129-1
Purine nucleobase transport in bloodstream forms of Trypanosoma brucei brucei is mediated by two novel transporters
H. D. Koning (1997)
10.1016/S0166-6851(99)00002-X
A tightly regulated inducible expression system for conditional gene knock-outs and dominant-negative genetics in Trypanosoma brucei.
E. Wirtz (1999)
10.1128/MCB.01496-08
Trypanosoma brucei Spliced Leader RNA Maturation by the Cap 1 2′-O-Ribose Methyltransferase and SLA1 H/ACA snoRNA Pseudouridine Synthase Complex
Jesse R. Zamudio (2008)
10.1021/BI990829U
Iminoribitol transition state analogue inhibitors of protozoan nucleoside hydrolases.
R. W. Miles (1999)
Characterisation of a nucleoside / proton symporter in procyclic Trypanosoma brucei brucei
V. Delespaux (2007)
10.1074/jbc.M109.049726
Predictive Computational Models of Substrate Binding by a Nucleoside Transporter*
C. Collar (2009)
10.1074/JBC.M105906200
Purine-less Death in Plasmodium falciparumInduced by Immucillin-H, a Transition State Analogue of Purine Nucleoside Phosphorylase*
G. Kicska (2002)
10.1124/mol.106.031351
Loss of the High-Affinity Pentamidine Transporter Is Responsible for High Levels of Cross-Resistance between Arsenical and Diamidine Drugs in African Trypanosomes
Daniel J. Bridges (2007)
10.1074/JBC.273.16.9486
Characterization of a Nucleoside/Proton Symporter in ProcyclicTrypanosoma brucei brucei *
H. D. de Koning (1998)
2007. 2,N 6 -Disubstituted adenosine analogues with antitrypanosomal and antimalarial activities
B Rodenko
Molecular cloning and expression of a purine-specific N-ribohydrolase from Trypanosoma brucei brucei. Sequence, expression, and molecular analysis
R. Pellé (1998)
10.1016/j.bmc.2008.05.056
N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase.
A. Goeminne (2008)
10.1016/J.EJMECH.2007.03.027
Synthesis and biochemical evaluation of guanidino-alkyl-ribitol derivatives as nucleoside hydrolase inhibitors.
A. Goeminne (2008)
10.1124/mol.106.031559
Molecular Interactions Underlying the Unusually High Adenosine Affinity of a Novel Trypanosoma brucei Nucleoside Transporter
Mohammed I. Al-Salabi (2007)
10.1016/S0163-7258(03)00071-8
Potential chemotherapeutic targets in the purine metabolism of parasites.
M. H. Kouni (2003)
10.1124/MOL.56.6.1162
Adenosine transporters in bloodstream forms of Trypanosoma brucei brucei: substrate recognition motifs and affinity for trypanocidal drugs.
H. D. de Koning (1999)
10.1517/13543776.15.8.987
Purine analogues as antiparasitic agents
P. Lawton (2005)
10.1128/AAC.00458-07
Adenosine Kinase of Trypanosoma brucei and Its Role in Susceptibility to Adenosine Antimetabolites
A. Lüscher (2007)
10.1006/JMBI.2001.4548
Structure and function of a novel purine specific nucleoside hydrolase from Trypanosoma vivax.
W. Versées (2001)
10.1126/SCIENCE.285.5425.242
A nucleoside transporter from Trypanosoma brucei involved in drug resistance.
P. Mäser (1999)



This paper is referenced by
10.1021/jm2014259
Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes.
Andrea Taladriz (2012)
Computational insight into the broad substrate specificity of enzymes that process nucleic acids
S. Lenz (2018)
10.1038/s41467-019-13522-6
Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
Fabian Hulpia (2019)
Pyrimidine salvage and metabolism in kinetoplastid parasites
Juma A. M. Ali (2013)
10.1074/jbc.M116.715615
Trypanosoma brucei Methylthioadenosine Phosphorylase Protects the Parasite from the Antitrypanosomal Effect of Deoxyadenosine
M. Vodnala (2016)
10.1016/j.ejmech.2018.12.050
Revisiting tubercidin against kinetoplastid parasites: Aromatic substitutions at position 7 improve activity and reduce toxicity.
Fabian Hulpia (2019)
10.1155/2020/9130719
In Silico Identification of New Targets for Diagnosis, Vaccine, and Drug Candidates against Trypanosoma cruzi
Rafael Obata Trevisan (2020)
10.1002/pro.3141
Structural and biochemical characterization of the nucleoside hydrolase from C. elegans reveals the role of two active site cysteine residues in catalysis
R. Singh (2017)
10.1371/journal.pone.0058034
Pyrimidine Biosynthesis Is Not an Essential Function for Trypanosoma brucei Bloodstream Forms
Juma A. M. Ali (2013)
10.1155/2015/826047
In Silico Investigation of Flavonoids as Potential Trypanosomal Nucleoside Hydrolase Inhibitors
C. Ha (2015)
10.1038/srep35894
Crystal structures and inhibition of Trypanosoma brucei hypoxanthine–guanine phosphoribosyltransferase
David Terán (2016)
10.2174/09298673113206660285
Transition-state-guided drug design for treatment of parasitic neglected tropical diseases.
A. S. Murkin (2014)
10.1111/cbdd.13341
Druggability of the guanosine/adenosine/cytidine nucleoside hydrolase from Trichomonas vaginalis
Rayyan Alam (2018)
10.1016/j.ijpddr.2017.04.003
Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy
Khalid J Alzahrani (2017)
10.1107/S0907444913010792
Structures of purine nucleosidase from Trypanosoma brucei bound to isozyme-specific trypanocidals and a novel metalorganic inhibitor.
F. Giannese (2013)
10.1124/mol.112.082321
Pyrimidine Salvage in Trypanosoma brucei Bloodstream Forms and the Trypanocidal Action of Halogenated Pyrimidines
Juma A. M. Ali (2013)
10.1016/j.bmcl.2017.05.052
Evaluation of the antiprotozoan properties of 5'-norcarbocyclic pyrimidine nucleosides.
Khalid J Alzahrani (2017)
10.1038/s41467-020-20035-0
Reverse C-glycosidase reaction provides C-nucleotide building blocks of xenobiotic nucleic acids
M. Pfeiffer (2020)
10.1016/j.bmc.2017.02.016
Synthesis and activity of nucleoside-based antiprotozoan compounds.
Huu-Anh Tran (2017)
10.1016/j.molbiopara.2018.01.005
Trypanosoma brucei bloodstream forms express highly specific and separate transporters for adenine and hypoxanthine; evidence for a new protozoan purine transporter family?
G. D. Campagnaro (2018)
Synthesis and Structure-Activity Analysis of New Phosphonium Salts with Potent Activity Against
Andrea Taladriz (2012)
10.1016/j.drudis.2020.02.008
Acyclic nucleoside phosphonates as possible chemotherapeutics against Trypanosoma brucei.
David Terán (2020)
10.1111/febs.14987
Crystal structures of Trypanosoma brucei hypoxanthine – guanine – xanthine phosphoribosyltransferase in complex with IMP, GMP and XMP
David Terán (2019)
10.1007/s10822-018-0178-y
Structural explanation for the tunable substrate specificity of an E. coli nucleoside hydrolase: insights from molecular dynamics simulations
Stefan A. P. Lenz (2018)
Ověření působení fosfanátů acyklických nukleosidů na fosforibozyl transferázy 6-oxo purinů u Trypanosomy brucei.
Z. Kotrbová (2012)
Vrije Universiteit Brussel Structure and mechanism of the 6-oxopurine nucleosidase from Trypanosoma brucei
An Vandemeulebroucke (2010)
10.1021/jm301059b
Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase B1.
K. Orrling (2012)
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