Table Info

Table 3.

ENTPDase inhibitors—non-nucleotide analogs

Derivatives class	Inhibitors	IC₅₀^a or Ki^b (µM)	Specificity	Applications	Experimental context
Polyoxometalates (POMs) [77–79]	POM-1	0.8000^b	N1 > N3 >> N2	Potential anticancer, cardiprotection. ENTPDases functional studies.	Inhibition assays with recombinant protein and in vitro assays using metastatic cells.
Polyoxometalates (POMs) [77–79]	PSB-POM142 (POM-5)	0.0039^b	N1 >> N2 > N3
Anthraquinone derivatives [73, 82]	PSB-069	15.70^a	N1 > N2 > N3	Therapeutic potential for treating neurodegenerative and neuroinflammatory diseases and inflammation.	In vitro inhibition assays using capillary electrophoresis (CE) and the malachite green assay (MG).
	PSB-071	12.80^a	N2 > N3 >> N1
	PSB-06126	1.500^a	N3
	PSB-16131	0.539^a	N2
	PSB-2020	0.551^a	N2
	PSB-1011	0.390^a	N3
	PSB-2046	0.723^a	N3
Tryptamine-derived Schiff bases [69]	C# 1	0.030^b	N1	Potential for use in the treatment of cancer and thrombosis.	Inhibition assays with recombinant enzymes (MG) and molecular docking.
	C# 4	0.080^b	N1
	C# 5	0.071^b	N3 > N1 = N8
	C# 13	0.280^b	N8
	C# 14	0.170^b	N3 > N1 > N8
	C# 22	0.490^b	N8
Thiadiazole pyrimidones [66]	8b	0.04^b	N1	Study of insulin secretion and purinergic modulation.	Inhibition assays with recombinant human enzymes (MG), docking studies, and in vitro tests on pancreatic islets.
	8c	0.03^b	N1 > N3 >> N8
	8f	0.03^b	N1
	8i	0.17^b	N2 > N1
	8j	0.02^b	N1 > N2
	8k	0.07^b	N2
	8m	0.16^b	N3 >> N1
Carboxamides [70]	2a	1.60^a	N8 > N2 > N3 > N1	Treatment of type 2 diabetes, inflammatory and metabolic disorders, and isoform-specific studies.	Inhibition assays with recombinant human enzymes (MG), in vitro tests on pancreatic islets, and molecular docking studies.
	2b	2.82^a	N3
	2d	0.15^a	N2 > N1
	2f	0.70^a	N1
	2h	0.12^a	N1
	2i	1.46^a	N1 > N3
Quinoline derivatives [80]	2c	0.86^a	N3 > N8 > N1	Therapeutic potential to treat cancer and other diseases associated with ENTPDase overexpression.	Inhibition assays with recombinant human enzymes (malachite green).
	2h	0.36^a	N3 > N1 > N2 > N8
	3b	0.55^a	N1 > N2
	3f	0.20^a	N1 > N3
	4	0.51^a	N3 > N1 > N2
	5c	0.65^{a (b)}	N8
Sulfopolysac-charides [85]	Compound 5	1.72^b	N1, but also inhibited NPP1 NPP1 > N1	Therapeutic potential to treat cancer.	Inhibition assays on enzymes (NTPDases and NPPs) and U87 glioblastoma cells using CE and MG.
	Compound 6	0.408^b
	Compound 7	12.3^b
Tienotetraidropirimidina derivatives [64]	Compound 32	45.2^a	Dual inhibitor for N1 (CD39) and CD73	Therapeutic potential to treat cancer.	Inhibition assays with recombinant enzymes using CE and MG.
Thiadiazole amide derivatives [83]	5a	0.05^a	N1 >> N2 > N8	Potential in cancer immunotherapy and the treatment of immunological and thrombotic diseases.	Inhibition assays with recombinant human enzymes (MG) and molecular docking studies.
	5b	0.06^a	N2 > N1
	5c	0.08^a	N2 > N1
	5e	0.05^a	N8 >> N1 > N3 >> N2
	5g	0.04^a	N2 >> N8
	5j	0.07^a	N8 >> N2 > N1 > N3
Glicinatos de tienopirimidina [84]	3j	0.11^a	N1	Potential in cancer immunotherapy and the treatment of inflammatory diseases, diabetes, and thrombosis.	Inhibition assays with recombinant human enzymes (MG) and molecular docking studies.
	3k	3.00^a	N3
	3l	1.00^a	N8 >> N1
	3n	0.40^a	N2
	4	0.13^a	N2
Protein kinase inhibitors [87]	Certinib	11.3^a	N1 >> N3 = N8	Potential in cancer immunotherapy and a basis for the development of new inhibitors.	Inhibition assays with recombinant and native enzymes (tumor cell cultures) using CE and MG.
Sulfamoyl benzamides [86]	2d	0.28^a	N8	Potential in cancer immunotherapy and the treatment of type 2 diabetes and thrombosis.	Inhibition assays with recombinant human enzymes (MG) and molecular docking studies.
	3f	0.27^a	N2 > N3
	3i	0.72^a	N3 > N1
	3j	0.29^a	N2 > N3
	4d	0.13^a	N2 > N3 > N8

N1, N2, N3, and N8 refer to NTPDases 1, 2, 3, and 8, respectively. CE: capillary electrophoresis; MG: malachite green method; ENTPDases: ectonucleoside triphosphate diphosphohydrolases; CD39: cluster of differentiation 39; NPP: nucleotide pyrophosphatase/phosphodiesterase

Declarations

Author contributions

ICR: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. ALdA: Writing—original draft. VdAR: Writing—original draft. MSLL: Writing—original draft. JLRF: Conceptualization, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The authors gratefully acknowledge the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the fellowship grants awarded to JLRF and ICR, which supported this study. This study was sponsored in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) [001]; Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [BPD-00498-22]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Zimmermann H. History of ectonucleotidases and their role in purinergic signaling. Biochem Pharmacol. 2021;187:114322. [DOI] [PubMed]

Zimmermann H, Zebisch M, Sträter N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal. 2012;8:437–502. [DOI] [PubMed] [PMC]

Robson SC, Sévigny J, Zimmermann H. The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance. Purinergic Signal. 2006;2:409–30. [DOI] [PubMed] [PMC]

Knowles AF. The GDA1_CD39 superfamily: NTPDases with diverse functions. Purinergic Signal. 2011;7:21–45. [DOI] [PubMed] [PMC]

Haas CB, Lovászi M, Braganhol E, Pacher P, Haskó G. Ectonucleotidases in Inflammation, Immunity, and Cancer. J Immunol. 2021;206:1983–90. [DOI] [PubMed] [PMC]

Haas CB, Lovászi M, Pacher P, de Souza PO, Pelletier J, Leite RO, et al. Extracellular ectonucleotidases are differentially regulated in murine tissues and human polymorphonuclear leukocytes during sepsis and inflammation. Purinergic Signal. 2021;17:713–24. [DOI] [PubMed] [PMC]

Kukulski F, Lévesque SA, Lavoie EG, Lecka J, Bigonnesse F, Knowles AF, et al. Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8. Purinergic Signal. 2005;1:193–204. [DOI] [PubMed] [PMC]

Fausther M, Lecka J, Kukulski F, Lévesque SA, Pelletier J, Zimmermann H, et al. Cloning, purification, and identification of the liver canalicular ecto-ATPase as NTPDase8. Am J Physiol Gastrointest Liver Physiol. 2007;292:G785–95. [DOI] [PubMed] [PMC]

Mateo J, Kreda S, Henry CE, Harden TK, Boyer JL. Requirement of Cys399 for processing of the human ecto-ATPase (NTPDase2) and its implications for determination of the activities of splice variants of the enzyme. J Biol Chem. 2003;278:39960–8. [DOI] [PubMed]

10.

Crawford PA, Gaddie KJ, Smith TM, Kirley TL. Characterization of an alternative splice variant of human nucleoside triphosphate diphosphohydrolase 3 (NTPDase3): a possible modulator of nucleotidase activity and purinergic signaling. Arch Biochem Biophys. 2007;457:7–15. [DOI] [PubMed] [PMC]

11.

Zebisch M, Sträter N. Structural insight into signal conversion and inactivation by NTPDase2 in purinergic signaling. Proc Natl Acad Sci U S A. 2008;105:6882–7. [DOI] [PubMed] [PMC]

12.

Morello S, Caiazzo E, Turiello R, Cicala C. Thrombo-Inflammation: A Focus on NTPDase1/CD39. Cells. 2021;10:2223. [DOI] [PubMed] [PMC]

13.

Marcus AJ, Broekman MJ, Drosopoulos JH, Olson KE, Islam N, Pinsky DJ, et al. Role of CD39 (NTPDase-1) in thromboregulation, cerebroprotection, and cardioprotection. Semin Thromb Hemost. 2005;31:234–46. [DOI] [PubMed]

14.

Sévigny J, Sundberg C, Braun N, Guckelberger O, Csizmadia E, Qawi I, et al. Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation. Blood. 2002;99:2801–9. [DOI] [PubMed]

15.

Antonioli L, Pacher P, Vizi ES, Haskó G. CD39 and CD73 in immunity and inflammation. Trends Mol Med. 2013;19:355–67. [DOI] [PubMed] [PMC]

16.

Vandenbeuch A, Anderson CB, Parnes J, Enjyoji K, Robson SC, Finger TE, et al. Role of the ectonucleotidase NTPDase2 in taste bud function. Proc Natl Acad Sci U S A. 2013;110:14789–94. [DOI] [PubMed] [PMC]

17.

Braun N, Sévigny J, Mishra SK, Robson SC, Barth SW, Gerstberger R, et al. Expression of the ecto-ATPase NTPDase2 in the germinal zones of the developing and adult rat brain. Eur J Neurosci. 2003;17:1355–64. [DOI] [PubMed]

18.

Braun N, Zimmermann H. Microglial ectonucleotidases: Identification and functional roles. Drug Dev Res. 2001;53:208–17. [DOI]

19.

Sandhu B, Perez-Matos MC, Tran S, Singhal G, Syed I, Feldbrügge L, et al. Global deletion of NTPDase3 protects against diet-induced obesity by increasing basal energy metabolism. Metabolism. 2021;118:154731. [DOI] [PubMed] [PMC]

20.

Grković I, Bjelobaba I, Mitrović N, Lavrnja I, Drakulić D, Martinović J, et al. Expression of ecto-nucleoside triphosphate diphosphohydrolase3 (NTPDase3) in the female rat brain during postnatal development. J Chem Neuroanat. 2016;77:10–8. [DOI] [PubMed]

21.

Vongtau HO, Lavoie EG, Sévigny J, Molliver DC. Distribution of ecto-nucleotidases in mouse sensory circuits suggests roles for nucleoside triphosphate diphosphohydrolase-3 in nociception and mechanoreception. Neuroscience. 2011;193:387–98. [DOI] [PubMed] [PMC]

22.

Salem M, Lecka J, Pelletier J, Gomes Marconato D, Dumas A, Vallières L, et al. NTPDase8 protects mice from intestinal inflammation by limiting P2Y₆receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD. Gut. 2022;71:43–54. [DOI] [PubMed]

23.

Voet S, Srinivasan S, Lamkanfi M, van Loo G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol Med. 2019;11:e10248. [DOI] [PubMed] [PMC]

24.

Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell. 2014;157:1013–22. [DOI] [PubMed]

25.

Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: a general review. Int J Neurosci. 2017;127:624–33. [DOI] [PubMed]

26.

Bulavina L, Szulzewsky F, Rocha A, Krabbe G, Robson SC, Matyash V, et al. NTPDase1 activity attenuates microglial phagocytosis. Purinergic Signal. 2013;9:199–205. [DOI] [PubMed] [PMC]

27.

Wink MR, Braganhol E, Tamajusuku AS, Lenz G, Zerbini LF, Libermann TA, et al. Nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) is the dominant ectonucleotidase expressed by rat astrocytes. Neuroscience. 2006;138:421–32. [DOI] [PubMed]

28.

Jakovljevic M, Lavrnja I, Bozic I, Milosevic A, Bjelobaba I, Savic D, et al. Induction of NTPDase1/CD39 by Reactive Microglia and Macrophages Is Associated With the Functional State During EAE. Front Neurosci. 2019;13:410. [DOI] [PubMed] [PMC]

29.

Pérez-Sen R, Queipo MJ, Morente V, Ortega F, Delicado EG, Miras-Portugal MT. Neuroprotection Mediated by P2Y13 Nucleotide Receptors in Neurons. Comput Struct Biotechnol J. 2015;13:160–8. [DOI] [PubMed] [PMC]

30.

Jakovljevic M, Lavrnja I, Bozic I, Savic D, Bjelobaba I, Pekovic S, et al. Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis. Front Cell Neurosci. 2017;11:333. [DOI] [PubMed] [PMC]

31.

Ansoleaga B, Jové M, Schlüter A, Garcia-Esparcia P, Moreno J, Pujol A, et al. Deregulation of purine metabolism in Alzheimer’s disease. Neurobiol Aging. 2015;36:68–80. [DOI] [PubMed]

32.

Bonan CD, Roesler R, Pereira GS, Battastini AM, Izquierdo I, Sarkis JJ. Learning-specific decrease in synaptosomal ATP diphosphohydrolase activity from hippocampus and entorhinal cortex of adult rats. Brain Res. 2000;854:253–6. [DOI] [PubMed]

33.

Tomczyk M, Glaser T, Slominska EM, Ulrich H, Smolenski RT. Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies. Int J Mol Sci. 2021;22:6545. [DOI] [PubMed] [PMC]

34.

Deaglio S, Robson SC. Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. Adv Pharmacol. 2011;61:301–32. [DOI] [PubMed] [PMC]

35.

Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets. Immunol Rev. 2017;276:121–44. [DOI] [PubMed] [PMC]

36.

da Silva W, da Rocha Torres N, de Melo Agripino J, da Silva VHF, de Souza ACA, Ribeiro IC, et al. ENTPDases from Pathogenic Trypanosomatids and Purinergic Signaling: Shedding Light towards Biotechnological Applications. Curr Top Med Chem. 2021;21:213–26. [DOI] [PubMed]

37.

Paes-Vieira L, Gomes-Vieira AL, Meyer-Fernandes JR. E-NTPDases: Possible Roles on Host-Parasite Interactions and Therapeutic Opportunities. Front Cell Infect Microbiol. 2021;11:769922. [DOI] [PubMed] [PMC]

38.

Eberhardt N, Bergero G, Mazzocco Mariotta YL, Aoki MP. Purinergic modulation of the immune response to infections. Purinergic Signal. 2022;18:93–113. [DOI] [PubMed] [PMC]

39.

Sansom FM. The role of the NTPDase enzyme family in parasites: what do we know, and where to from here? Parasitology. 2012;139:963–80. [DOI] [PubMed]

40.

de Carvalho LSA, Alves Jr Ij, Junqueira LR, Silva LM, Riani LR, de Faria Pinto P, et al. ATP-Diphosphohydrolases in Parasites: Localization, Functions and Recent Developments in Drug Discovery. Curr Protein Pept Sci. 2019;20:873–84. [DOI] [PubMed]

41.

Lauri N, Bazzi Z, Alvarez CL, Leal Denis MF, Schachter J, Herlax V, et al. ATPe Dynamics in Protozoan Parasites. Adapt or Perish. Genes (Basel). 2018;10:16. [DOI] [PubMed] [PMC]

42.

Tonin AA, Da Silva AS, Zanini D, Pelinson LP, Schetinger MRC, Camillo G, et al. Biochemical detection of enzymes NTPDase in tachyzoites of Toxoplasma gondii and possible functional correlations. Comp Clin Path. 2015;24:393–7. [DOI]

43.

Alves VS, Leite-Aguiar R, Silva JPD, Coutinho-Silva R, Savio LEB. Purinergic signaling in infectious diseases of the central nervous system. Brain Behav Immun. 2020;89:480–90. [DOI] [PubMed] [PMC]

44.

Ferla M, Tasca T. The Role of Purinergic Signaling in Trichomonas vaginalis Infection. Curr Top Med Chem. 2021;21:181–92. [DOI] [PubMed]

45.

Frasson AP, De Carli GA, Bonan CD, Tasca T. Involvement of purinergic signaling on nitric oxide production by neutrophils stimulated with Trichomonas vaginalis. Purinergic Signal. 2012;8:1–9. [DOI] [PubMed] [PMC]

46.

al-Rashida M, Iqbal J. Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5’-nucleotidase, and alkaline phosphatase inhibitors. Med Res Rev. 2014;34:703–43. [DOI] [PubMed]

47.

Santos RF, Pôssa MAS, Bastos MS, Guedes PMM, Almeida MR, DeMarco R, et al. Influence of Ecto-Nucleoside Triphosphate Diphosphohydrolase Activity on Trypanosoma cruzi Infectivity and Virulence. PLoS Negl Trop Dis. 2009;3:e387. [DOI]

48.

Mariotini-Moura C, Silva e Bastos M, de Castro FF, Trindade ML, Vasconcellos Rde S, Neves-do-Valle MA, et al. Trypanosoma cruzi nucleoside triphosphate diphosphohydrolase 1 (TcNTPDase-1) biochemical characterization, immunolocalization and possible role in host cell adhesion. Acta Trop. 2014;130:140–7. [DOI] [PubMed]

49.

Paes-Vieira L, Gomes-Vieira AL, Meyer-Fernandes JR. NTPDase activities: possible roles on Leishmania spp infectivity and virulence. Cell Biol Int. 2018;42:670–82. [DOI] [PubMed]

50.

Chaves M, Savio LE, Coutinho-Silva R. Purinergic signaling: A new front-line determinant of resistance and susceptibility in leishmaniasis. Biomed J. 2022;45:109–17. [DOI] [PubMed] [PMC]

51.

da Silva W, Ribeiro IC, Agripino JM, da Silva VHF, de Souza LÂ, Oliveira TA, et al. Leishmania infantum NTPDase1 and NTPDase2 play an important role in infection and nitric oxide production in macrophages. Acta Trop. 2023;237:106732. [DOI] [PubMed]

52.

Fracasso M, Reichert K, Bottari NB, da Silva AD, Schetinger MRC, Monteiro SG, et al. Involvement of ectonucleotidases and purinergic receptor expression during acute Chagas disease in the cortex of mice treated with resveratrol and benznidazole. Purinergic Signal. 2021;17:493–502. [DOI] [PubMed] [PMC]

53.

Silva-Gomes NLD, Ruivo LAS, Moreira C, Meuser-Batista M, Silva CFD, Batista DDGJ, et al. Overexpression of TcNTPDase-1 Gene Increases Infectivity in Mice Infected with Trypanosoma cruzi. Int J Mol Sci. 2022;23:14661. [DOI] [PubMed] [PMC]

54.

Souza Vdo C, Schlemmer KB, Noal CB, Jaques JA, Zimmermann CE, Leal CA, et al. E-NTPDase and E-ADA activities are altered in lymphocytes of patients with indeterminate form of Chagas’ disease. Parasitol Int. 2012;61:690–6. [DOI] [PubMed]

55.

Levano-Garcia J, Dluzewski AR, Markus RP, Garcia CR. Purinergic signalling is involved in the malaria parasite Plasmodium falciparum invasion to red blood cells. Purinergic Signal. 2010;6:365–72. [DOI] [PubMed] [PMC]

56.

Borges-Pereira L, Meissner KA, Wrenger C, Garcia CRS. Plasmodium falciparum GFP-E-NTPDase expression at the intraerythrocytic stages and its inhibition blocks the development of the human malaria parasite. Purinergic Signal. 2017;13:267–77. [DOI] [PubMed] [PMC]

57.

Wang C, Yu L, Zhang J, Zhou Y, Sun B, Xiao Q, et al. Structural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1. Nat Commun. 2023;14:1727. [DOI] [PubMed] [PMC]

58.

Huber SM. Purinoceptor signaling in malaria-infected erythrocytes. Microbes Infect. 2012;14:779–86. [DOI] [PubMed]

59.

Bastos MS, Tremblay A, Agripino JM, Rabelo ILA, Barreto LP, Pelletier J, et al. The expression of NTPDase1 and -2 of Leishmania infantum chagasi in bacterial and mammalian cells: Comparative expression, refolding and nucleotidase characterization. Protein Expr Purif. 2017;131:60–9. [DOI] [PubMed]

60.

Nation CS, Da’Dara AA, Skelly PJ. NAD-catabolizing ectoenzymes of Schistosoma mansoni. Biochem J. 2022;479:1165–80. [DOI] [PubMed]

61.

Oliveira SD, Oliveira NF, Meyer-Fernandes JR, Savio LE, Ornelas FG, Ferreira ZS, et al. Increased expression of NTPDases 2 and 3 in mesenteric endothelial cells during schistosomiasis favors leukocyte adhesion through P2Y1 receptors. Vascul Pharmacol. 2016;82:66–72. [DOI] [PubMed]

62.

Pacheco PAF, Dantas LP, Ferreira LGB, Faria RX. Purinergic receptors and neglected tropical diseases: why ignore purinergic signaling in the search for new molecular targets? J Bioenerg Biomembr. 2018;50:307–13. [DOI] [PubMed]

63.

Oliveira NF, Silva CLM. Unveiling the Potential of Purinergic Signaling in Schistosomiasis Treatment. Curr Top Med Chem. 2021;21:193–204. [DOI] [PubMed]

64.

Schäkel L, Mirza S, Pietsch M, Lee SY, Keuler T, Sylvester K, et al. 2-Substituted thienotetrahydropyridine derivatives: Allosteric ectonucleotidase inhibitors. Arch Pharm (Weinheim). 2021;354:e2100300. [DOI] [PubMed]

65.

Allard D, Allard B, Stagg J. On the mechanism of anti-CD39 immune checkpoint therapy. J Immunother Cancer. 2020;8:e000186. [DOI] [PubMed] [PMC]

66.

Afzal S, Al-Rashida M, Hameed A, Pelletier J, Sévigny J, Iqbal J. Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases. Front Pharmacol. 2020;11:585876. [DOI] [PubMed] [PMC]

67.

Zimmermann H. Ectonucleoside triphosphate diphosphohydrolases and ecto-5’-nucleotidase in purinergic signaling: how the field developed and where we are now. Purinergic Signal. 2021;17:117–25. [DOI] [PubMed] [PMC]

68.

Baqi Y. Ecto-nucleotidase inhibitors: recent developments in drug discovery. Mini Rev Med Chem. 2015;15:21–33. [DOI] [PubMed]

69.

Kanwal, Mohammed Khan K, Salar U, Afzal S, Wadood A, Taha M, et al. Schiff bases of tryptamine as potent inhibitors of nucleoside triphosphate diphosphohydrolases (NTPDases): Structure-activity relationship. Bioorg Chem. 2019;82:253–66. [DOI] [PubMed]

70.

Afzal S, Al-Rashida M, Hameed A, Pelletier J, Sévigny J, Iqbal J. Synthesis, In-vitro evaluation and molecular docking studies of oxoindolin phenylhydrazine carboxamides as potent and selective inhibitors of ectonucleoside triphosphate diphosphohydrolase (NTPDase). Bioorg Chem. 2021;112:104957. [DOI] [PubMed]

71.

Munkonda MN, Kauffenstein G, Kukulski F, Lévesque SA, Legendre C, Pelletier J, et al. Inhibition of human and mouse plasma membrane bound NTPDases by P2 receptor antagonists. Biochem Pharmacol. 2007;74:1524–34. [DOI] [PubMed]

72.

Gendron FP, Halbfinger E, Fischer B, Beaudoin AR. Inhibitors of NTPDase: key players in the metabolism of extracellular purines. Adv Exp Med Biol. 2000;486:119–23. [DOI] [PubMed]

73.

Baqi Y, Weyler S, Iqbal J, Zimmermann H, Müller CE. Structure-activity relationships of anthraquinone derivatives derived from bromaminic acid as inhibitors of ectonucleoside triphosphate diphosphohydrolases (E-NTPDases). Purinergic Signal. 2009;5:91–106. [DOI] [PubMed] [PMC]

74.

Gendron FP, Halbfinger E, Fischer B, Duval M, D’Orléans-Juste P, Beaudoin AR. Novel inhibitors of nucleoside triphosphate diphosphohydrolases: chemical synthesis and biochemical and pharmacological characterizations. J Med Chem. 2000;43:2239–47. [DOI] [PubMed]

75.

Brunschweiger A, Iqbal J, Umbach F, Scheiff AB, Munkonda MN, Sévigny J, et al. Selective nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) inhibitors: nucleotide mimetics derived from uridine-5’-carboxamide. J Med Chem. 2008;51:4518–28. [DOI] [PubMed] [PMC]

76.

Ghiringhelli F, Bruchard M, Chalmin F, Rébé C. Production of adenosine by ectonucleotidases: a key factor in tumor immunoescape. J Biomed Biotechnol. 2012;2012:473712. [DOI] [PubMed] [PMC]

77.

Wall MJ, Wigmore G, Lopatár J, Frenguelli BG, Dale N. The novel NTPDase inhibitor sodium polyoxotungstate (POM-1) inhibits ATP breakdown but also blocks central synaptic transmission, an action independent of NTPDase inhibition. Neuropharmacology. 2008;55:1251–8. [DOI] [PubMed]

78.

Müller CE, Iqbal J, Baqi Y, Zimmermann H, Röllich A, Stephan H. Polyoxometalates--a new class of potent ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitors. Bioorg Med Chem Lett. 2006;16:5943–7. [DOI] [PubMed]

79.

Lee SY, Fiene A, Li W, Hanck T, Brylev KA, Fedorov VE, et al. Polyoxometalates--potent and selective ecto-nucleotidase inhibitors. Biochem Pharmacol. 2015;93:171–81. [DOI] [PubMed]

80.

Murtaza A, Afzal S, Zaman G, Saeed A, Pelletier J, Sévigny J, et al. Divergent synthesis and elaboration of structure activity relationship for quinoline derivatives as highly selective NTPDase inhibitor. Bioorg Chem. 2021;115:105240. [DOI] [PubMed]

81.

Hayat K, Afzal S, Saeed A, Murtaza A, Ur Rahman S, Khan KM, et al. Investigation of new quinoline derivatives as promising inhibitors of NTPDases: Synthesis, SAR analysis and molecular docking studies. Bioorg Chem. 2019;87:218–26. [DOI] [PubMed]

82.

Baqi Y, Rashed M, Schäkel L, Malik EM, Pelletier J, Sévigny J, et al. Development of Anthraquinone Derivatives as Ectonucleoside Triphosphate Diphosphohydrolase (NTPDase) Inhibitors With Selectivity for NTPDase2 and NTPDase3. Front Pharmacol. 2020;11:1282. [DOI] [PubMed] [PMC]

83.

Abbas S, Afzal S, Nadeem H, Hussain D, Langer P, Sévigny J, et al. Synthesis, characterization and biological evaluation of thiadiazole amide derivatives as nucleoside triphosphate diphosphohydrolases (NTPDases) inhibitors. Bioorg Chem. 2022;118:105456. [DOI] [PubMed]

84.

Begum Z, Ullah S, Akram M, Uzair M, Ullah F, Ahsanullah, et al. Identification of thienopyrimidine glycinates as selective inhibitors for h-NTPDases. Bioorg Chem. 2022;129:106196. [DOI] [PubMed]

85.

Lopez V, Schäkel L, Schuh HJM, Schmidt MS, Mirza S, Renn C, et al. Sulfated Polysaccharides from Macroalgae Are Potent Dual Inhibitors of Human ATP-Hydrolyzing Ectonucleotidases NPP1 and CD39. Mar Drugs. 2021;19:51. [DOI] [PubMed] [PMC]

86.

Zaigham ZH, Ullah S, Pelletier J, Sévigny J, Iqbal J, Hassan A. Synthesis and biological evaluation of sulfamoyl benzamide derivatives as selective inhibitors for h-NTPDases. RSC Adv. 2023;13:20909–15. [DOI] [PubMed] [PMC]

87.

Schäkel L, Mirza S, Winzer R, Lopez V, Idris R, Al-Hroub H, et al. Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 - a promising target for cancer immunotherapy. J Immunother Cancer. 2022;10:e004660. [DOI] [PubMed] [PMC]

88.

Pelletier J, Salem M, Lecka J, Fausther M, Bigonnesse F, Sévigny J. Generation and Characterization of Specific Antibodies to the Murine and Human Ectonucleotidase NTPDase8. Front Pharmacol. 2017;8:115. [DOI] [PubMed] [PMC]

89.

Pelletier J, Agonsanou H, Delvalle N, Fausther M, Salem M, Gulbransen B, et al. Generation and characterization of polyclonal and monoclonal antibodies to human NTPDase2 including a blocking antibody. Purinergic Signal. 2017;13:293–304. [DOI] [PubMed] [PMC]

90.

Munkonda MN, Pelletier J, Ivanenkov VV, Fausther M, Tremblay A, Künzli B, et al. Characterization of a monoclonal antibody as the first specific inhibitor of human NTP diphosphohydrolase-3: partial characterization of the inhibitory epitope and potential applications. FEBS J. 2009;276:479–96. [DOI] [PubMed] [PMC]

91.

Zhang H, Vijayan D, Li XY, Robson SC, Geetha N, Teng MWL, et al. The role of NK cells and CD39 in the immunological control of tumor metastases. Oncoimmunology. 2019;8:e1593809. [DOI] [PubMed] [PMC]

92.

Novaes RD, Santos EC, Cupertino MC, Bastos DSS, Mendonça AAS, Marques-da-Silva EA, et al. Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by Enhancing Parasitism, Inflammation, and Reactive Tissue Damage in Trypanosoma cruzi-Infected Mice. Oxid Med Cell Longev. 2018;2018:7385639. [DOI] [PubMed] [PMC]

93.

Ribeiro IC, de Moraes JVB, Mariotini-Moura C, Polêto MD, da Rocha Torres Pavione N, de Castro RB, et al. Synthesis of new non-natural L-glycosidic flavonoid derivatives and their evaluation as inhibitors of Trypanosoma cruzi ecto-nucleoside triphosphate diphosphohydrolase 1 (TcNTPDase1). Purinergic Signal. 2024;20:399–419. [DOI] [PubMed] [PMC]

94.

Vasconcellos Rde S, Mariotini-Moura C, Gomes RS, Serafim TD, Firmino Rde C, Silva E Bastos M, et al. Leishmania infantum ecto-nucleoside triphosphate diphosphohydrolase-2 is an apyrase involved in macrophage infection and expressed in infected dogs. PLoS Negl Trop Dis. 2014;8:e3309. [DOI] [PubMed] [PMC]

95.

Luiz Oliveira Penido M, Resende DM, Vianello MA, Humberto da Silveira Bordin F, Jacinto AA, Dias WD, et al. A new series of schistosomicide drugs, the alkylaminoalkanethiosulfuric acids, partially inhibit the activity of Schistosoma mansoni ATP diphosphohydrolase. Eur J Pharmacol. 2007;570:10–7. [DOI] [PubMed]

96.

de Carvalho LSA, Silva LM, de Souza VC, da Silva MPN, Capriles PVSZ, de Faria Pinto P, et al. Cardamonin Presents in Vivo Activity against Schistosoma mansoni and Inhibits Potato Apyrase. Chem Biodivers. 2021;18:e2100604. [DOI] [PubMed]

97.

de Castro CC, Costa PS, Laktin GT, de Carvalho PH, Geraldo RB, de Moraes J, et al. Cardamonin, a schistosomicidal chalcone from Piper aduncum L. (Piperaceae) that inhibits Schistosoma mansoni ATP diphosphohydrolase. Phytomedicine. 2015;22:921–8. [DOI] [PubMed]

98.

Bottari NB, Reichert KP, Fracasso M, Dutra A, Assmann CE, Ulrich H, et al. Neuroprotective role of resveratrol mediated by purinergic signalling in cerebral cortex of mice infected by Toxoplasma gondii. Parasitol Res. 2020;119:2897–905. [DOI] [PubMed]

99.

Frasson AP, Menezes CB, Goelzer GK, Gnoatto SCB, Garcia SC, Tasca T. Adenosine reduces reactive oxygen species and interleukin-8 production by Trichomonas vaginalis-stimulated neutrophils. Purinergic Signal. 2017;13:569–77. [DOI] [PubMed] [PMC]

100.

Giordani RB, Weizenmann M, Rosemberg DB, De Carli GA, Bogo MR, Zuanazzi JA, et al. Trichomonas vaginalis nucleoside triphosphate diphosphohydrolase and ecto-5’-nucleotidase activities are inhibited by lycorine and candimine. Parasitol Int. 2010;59:226–31. [DOI] [PubMed]

101.

Petró-Silveira B, Rigo GV, da Silva Trentin D, Macedo AJ, Sauer E, de Oliveira Alves E, et al. Trichomonas vaginalis NTPDase inhibited by lycorine modulates the parasite-neutrophil interaction. Parasitol Res. 2020;119:2587–95. [DOI] [PubMed]

102.

Iqbal J, Shah SJA. Molecular dynamic simulations reveal structural insights into substrate and inhibitor binding modes and functionality of Ecto-Nucleoside Triphosphate Diphosphohydrolases. Sci Rep. 2018;8:2581. [DOI] [PubMed] [PMC]

103.

Zebisch M, Baqi Y, Schäfer P, Müller CE, Sträter N. Crystal structure of NTPDase2 in complex with the sulfoanthraquinone inhibitor PSB-071. J Struct Biol. 2014;185:336–41. [DOI] [PubMed]

104.

Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases. J Control Release. 2016;235:34–47. [DOI] [PubMed]