Artículo

Szajnman, S.H.; Galaka, T.; Li, Z.-H.; Li, C.; Howell, N.M.; Chao, M.N.; Striepen, B.; Muralidharan, V.; Moreno, S.N.J.; Rodriguez, J.B."In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites" (2017) Antimicrobial Agents and Chemotherapy. 61(2)
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

We tested a series of sulfur-containing linear bisphosphonates against Toxoplasma gondii, the etiologic agent of toxoplasmosis. The most potent compound (compound 22; 1-[(n-decylsulfonyl)ethyl]-1,1-bisphosphonic acid) is a sulfonecontaining compound, which had a 50% effective concentration (EC50) of 0.11 ± 0.02 μM against intracellular tachyzoites. The compound showed low toxicity when tested in tissue culture with a selectivity index of >2,000. Compound 22 also showed high activity in vivo in a toxoplasmosis mouse model. The compound inhibited the Toxoplasma farnesyl diphosphate synthase (TgFPPS), but the concentration needed to inhibit 50% of the enzymatic activity (IC50) was higher than the concentration that inhibited 50% of growth. We tested compound 22 against two other apicomplexan parasites, Plasmodium falciparum (EC50 of 0.6 ± 0.01 μM), the agent of malaria, and Cryptosporidium parvum (EC50 of ∼65 μM), the agent of cryptosporidiosis. Our results suggest that compound 22 is an excellent novel compound that could lead to the development of potent agents against apicomplexan parasites. © 2017 American Society for Microbiology. All Rights Reserved.

Registro:

Documento: Artículo
Título:In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites
Autor:Szajnman, S.H.; Galaka, T.; Li, Z.-H.; Li, C.; Howell, N.M.; Chao, M.N.; Striepen, B.; Muralidharan, V.; Moreno, S.N.J.; Rodriguez, J.B.
Filiación:Departamento de Química Orgánica, UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA, United States
Palabras clave:Bisphosphonates; Cryptosporidium parvum; Farnesyl diphosphate synthase; Isoprenoids; Plasmodium falciparum; Toxoplasma gondii; (2,2 diphosphonoethyl)(methyl)(hexyl)sulfonium tetrafluoroborate; (2,2 diphosphonoethyl)(methyl)(pentyl)sulfonium tetrafluoroborate; 1 [(n decylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n heptylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n hexylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n nonylsulfonyl)ethyl] 1,1 biphosphonic acid; 1 [(n octylsulfonyl)ethyl] 1,1 biphosphonic acid; atorvastatin; bisphosphonic acid derivative; geranyltransferase; hydroxymethylglutaryl coenzyme A reductase inhibitor; pamidronic acid; risedronic acid; sulfone; sulfur; unclassified drug; zoledronic acid; antiprotozoal agent; bisphosphonic acid derivative; enzyme inhibitor; sulfur; animal cell; animal experiment; animal model; Apicomplexa; Article; controlled study; cryptosporidiosis; Cryptosporidium parvum; EC50; enzyme activity; experimental model; IC50; in vitro study; in vivo study; malaria; mouse; nonhuman; Plasmodium falciparum; priority journal; selectivity index; tachyzoite; tissue culture; toxicity; Toxoplasma; toxoplasmosis; animal; antagonists and inhibitors; chemistry; dose response; drug effects; enzymology; growth, development and aging; human; inbred mouse strain; preclinical study; procedures; synthesis; toxoplasmosis; Animals; Antiprotozoal Agents; Chemistry Techniques, Synthetic; Cryptosporidium parvum; Diphosphonates; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Geranyltranstransferase; Humans; Mice, Inbred Strains; Plasmodium falciparum; Sulfur; Toxoplasma; Toxoplasmosis
Año:2017
Volumen:61
Número:2
DOI: http://dx.doi.org/10.1128/AAC.01590-16
Handle:http://hdl.handle.net/20.500.12110/paper_00664804_v61_n2_p_Szajnman
Título revista:Antimicrobial Agents and Chemotherapy
Título revista abreviado:Antimicrob. Agents Chemother.
ISSN:00664804
CODEN:AMACC
CAS:atorvastatin, 134523-00-5, 134523-03-8; geranyltransferase, 37277-79-5, 50812-36-7; pamidronic acid, 40391-99-9, 57248-88-1; risedronic acid, 105462-24-6, 122458-82-6; sulfone, 67015-63-8; sulfur, 13981-57-2, 7704-34-9; zoledronic acid, 118072-93-8, 131654-46-1, 165800-06-6, 165800-07-7; Antiprotozoal Agents; Diphosphonates; Enzyme Inhibitors; Geranyltranstransferase; Sulfur
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00664804_v61_n2_p_Szajnman

Referencias:

  • Luft, B.J., Hafner, R., Korzun, A.H., Leport, C., Antoniskis, D., Bosler, E.M., Bourland, D.D., III, Jacobson, J., Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome (1993) N Engl J Med, 329, pp. 995-1000. , https://doi.org/10.1056/NEJM199309303291403
  • Israelski, D.M., Remington, J.S., Toxoplasmosis in patients with cancer (1993) Clin Infect Dis, 17, pp. S423-S435. , https://doi.org/10.1093/clinids/17.Supplement_2.S423
  • Wong, S.Y., Remington, J.S., Toxoplasmosis in pregnancy (1994) Clin Infect Dis, 18, pp. 853-861. , https://doi.org/10.1093/clinids/18.6.853
  • Holland, G.N., Ocular toxoplasmosis: A global reassessment. Part II: Disease manifestations and management (2004) Am J Ophthalmol, 137, pp. 1-17
  • Dyer, O., Company reneges on promise to cut price of toxoplasmosis drug (2015) BMJ, 351, p. h6472. , https://doi.org/10.1136/bmj.h6472
  • Rodriguez, J.B., Szajnman, S.H., New antibacterials for the treatment of toxoplasmosis; A patent review (2012) Expert Opin Ther Pat, 22, pp. 311-333. , https://doi.org/10.1517/13543776.2012.668886
  • Davies, A.P., Chalmers, R.M., Cryptosporidiosis (2009) BMJ, 339, p. b4168. , https://doi.org/10.1136/bmj.b4168
  • (2014) World Malaria Report 2014, , WHO, World Health Organization, Geneva, Switzerland
  • Docampo, R., Moreno, S.N., Bisphosphonates as chemotherapeutic agents against trypanosomatid and apicomplexan parasites (2001) Curr Drug Targets Infect Disord, 1, pp. 51-61. , https://doi.org/10.2174/1568005013343191
  • Moreno, S.N., Li, Z.H., Anti-infectives targeting the isoprenoid pathway of Toxoplasma gondii (2008) Expert Opin Ther Targets, 12, pp. 253-263. , https://doi.org/10.1517/14728222.12.3.253
  • Nair, S.C., Brooks, C.F., Goodman, C.D., Sturm, A., McFadden, G.I., Sundriyal, S., Anglin, J.L., Striepen, B., Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii (2011) J Exp Med, 208, pp. 1547-1559. , https://doi.org/10.1084/jem.20110039
  • Ling, Y., Li, Z.H., Miranda, K., Oldfield, E., Moreno, S.N., The farnesyldiphosphate/ geranylgeranyl-diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and a molecular target of bisphosphonates (2007) J Biol Chem, 282, pp. 30804-30816. , https://doi.org/10.1074/jbc.M703178200
  • Li, Z.H., Cintron, R., Koon, N.A., Moreno, S.N., The N terminus and the chain-length determination domain play a role in the length of the isoprenoid product of the bifunctional Toxoplasma gondii farnesyl diphosphate synthase (2012) Biochemistry, 51, pp. 7533-7540. , https://doi.org/10.1021/bi3005335
  • Li, Z.H., Ramakrishnan, S., Striepen, B., Moreno, S.N., Toxoplasma gondii relies on both host and parasite isoprenoids and can be rendered sensitive to atorvastatin (2013) PLoS Pathog, 9. , https://doi.org/10.1371/journal.ppat.1003665
  • Rodan, G.A., Mechanisms of action of bisphosphonates (1998) Annu Rev Pharmacol Toxicol, 38, pp. 375-388. , https://doi.org/10.1146/annurev.pharmtox.38.1.375
  • Russell, R.G., Bisphosphonates: The first 40 years (2011) Bone, 49, pp. 2-19. , https://doi.org/10.1016/j.bone.2011.04.022
  • Reddy, R., Dietrich, E., Lafontaine, Y., Houghton, T.J., Belanger, O., Dubois, A., Arhin, F.F., Rafai Far, A., Bisphosphonated benzoxazinorifamycin prodrugs for the prevention and treatment of osteomyelitis (2008) Chem Med Chem, 3, pp. 1863-1868. , https://doi.org/10.1002/cmdc.200800255
  • Miller, K., Erez, R., Segal, E., Shabat, D., Satchi-Fainaro, R., Targeting bone metastases with a bispecific anticancer and antiangiogenic polymeralendronate-taxane conjugate (2009) Angew Chem Int Ed Engl, 48, pp. 2949-2954. , https://doi.org/10.1002/anie.200805133
  • Sanders, J.M., Ghosh, S., Chan, J.M., Meints, G., Wang, H., Raker, A.M., Song, Y., Oldfield, E., Quantitative structure-activity relationships for - T cell activation by bisphosphonates (2004) J Med Chem, 47, pp. 375-384. , https://doi.org/10.1021/jm0303709
  • Linares, G.E., Ravaschino, E.L., Rodriguez, J.B., Progresses in the field of drug design to combat tropical protozoan parasitic diseases (2006) Curr Med Chem, 13, pp. 335-360. , https://doi.org/10.2174/092986706775476043
  • Urbina, J.A., Moreno, B., Vierkotter, S., Oldfield, E., Payares, G., Sanoja, C., Bailey, B.N., Docampo, R., Trypanosoma cruzi contains major pyrophosphate stores, and its growth in vitro and in vivo is blocked by pyrophosphate analogs (1999) J Biol Chem, 274, pp. 33609-33615. , https://doi.org/10.1074/jbc.274.47.33609
  • Martin, M.B., Grimley, J.S., Lewis, J.C., Heath, H.T., III, Bailey, B.N., Kendrick, H., Yardley, V., Oldfield, E., Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: A potential route to chemotherapy (2001) J Med Chem, 44, pp. 909-916. , https://doi.org/10.1021/jm0002578
  • Martin, M.B., Arnold, W., Heath, H.T., III, Urbina, J.A., Oldfield, E., Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis (1999) Biochem Biophys Res Commun, 263, pp. 754-758. , https://doi.org/10.1006/bbrc.1999.1404
  • Szajnman, S.H., Bailey, B.N., Docampo, R., Rodriguez, J.B., Bisphosphonates derived from fatty acids are potent growth inhibitors of Trypanosoma cruzi (2001) Bioorg Med Chem Lett, 11, pp. 789-792. , https://doi.org/10.1016/S0960-894X(01)00057-9
  • Szajnman, S.H., Montalvetti, A., Wang, Y., Docampo, R., Rodriguez, J.B., Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase (2003) Bioorg Med Chem Lett, 13, pp. 3231-3235. , https://doi.org/10.1016/S0960-894X(03)00663-2
  • Szajnman, S.H., Ravaschino, E.L., Docampo, R., Rodriguez, J.B., Synthesis and biological evaluation of 1-amino-1,1-bisphosphonates derived from fatty acids against Trypanosoma cruzi targeting farnesyl pyrophosphate synthase (2005) Bioorg Med Chem Lett, 15, pp. 4685-4690. , https://doi.org/10.1016/j.bmcl.2005.07.060
  • Ling, Y., Sahota, G., Odeh, S., Chan, J.M., Araujo, F.G., Moreno, S.N., Oldfield, E., Bisphosphonate inhibitors of Toxoplasma gondii growth: In vitro, QSAR, and in vivo investigations (2005) J Med Chem, 48, pp. 3130-3140. , https://doi.org/10.1021/jm040132t
  • Sun, S., McKenna, C.E., Farnesyl pyrophosphate synthase modulators: A patent review (2006-2010) (2011) Expert Opin Ther Pat, 21, pp. 1433-1451. , https://doi.org/10.1517/13543776.2011.593511
  • Recher, M., Barboza, A.P., Li, Z.H., Galizzi, M., Ferrer-Casal, M., Szajnman, S.H., Docampo, R., Rodriguez, J.B., Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents (2013) Eur J Med Chem, 60, pp. 431-440. , https://doi.org/10.1016/j.ejmech.2012.12.015
  • Aripirala, S., Szajnman, S.H., Jakoncic, J., Rodriguez, J.B., Docampo, R., Gabelli, S.B., Amzel, L.M., Design, synthesis, calorimetry, and crystallographic analysis of 2-alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase (2012) J Med Chem, 55, pp. 6445-6454. , https://doi.org/10.1021/jm300425y
  • Urbina, J.A., Concepcion, J.L., Montalvetti, A., Rodriguez, J.B., Docampo, R., Mechanism of action of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the causative agent of Chagas' disease (2003) Antimicrob Agents Chemother, 47, pp. 2047-2050. , https://doi.org/10.1128/AAC.47.6.2047-2050.2003
  • Elicio, P.D., Chao, M.N., Galizzi, M., Li, C., Szajnman, S.H., Docampo, R., Moreno, S.N., Rodriguez, J.B., Design, synthesis and biological evaluation of WC-9 analogs as antiparasitic agents (2013) Eur J Med Chem, 69, pp. 480-489. , https://doi.org/10.1016/j.ejmech.2013.09.009
  • Shang, N., Li, Q., Ko, T.P., Chan, H.C., Li, J., Zheng, Y., Huang, C.H., Guo, R.T., Squalene synthase as a target for Chagas disease therapeutics (2014) PLoS Pathog, 10. , https://doi.org/10.1371/journal.ppat.1004114
  • Chao, M.N., Matiuzzi, C.E., Storey, M., Li, C., Szajnman, S.H., Docampo, R., Moreno, S.N., Rodriguez, J.B., Aryloxyethyl thiocyanates are potent growth inhibitors of Trypanosoma cruzi and Toxoplasma gondii (2015) ChemMedChem, 10, pp. 1094-1108. , https://doi.org/10.1002/cmdc.201500100
  • Artz, J.D., Wernimont, A.K., Dunford, J.E., Schapira, M., Dong, A., Zhao, Y., Lew, J., Hui, R., Molecular characterization of a novel geranylgeranyl pyrophosphate synthase from Plasmodium parasites (2011) J Biol Chem, 286, pp. 3315-3322. , https://doi.org/10.1074/jbc.M109.027235
  • Artz, J.D., Dunford, J.E., Arrowood, M.J., Dong, A., Chruszcz, M., Kavanagh, K.L., Minor, W., Hui, R., Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis (2008) Chem Biol, 15, pp. 1296-1306. , https://doi.org/10.1016/j.chembiol.2008.10.017
  • Yardley, V.K.A., Martin, M.B., Slifer, T.R., Araujo, F.G., Moreno, S.N., Docampo, R., Croft, S.L., Oldfield, E., In vivo activities of farnesyl pyrophosphate synthase inhibitors against Leishmania donovani and Toxoplasma gondii (2002) Antimicrob Agents Chemother, 46, pp. 929-931. , https://doi.org/10.1128/AAC.46.3.929-931.2002
  • Aversa, M.C., Barattucci, A., Bilardo, M.C., Bonaccorsi, P., Giannetto, P., Rollin, P., Tatibouet, A., Sulfenic acids in the carbohydrate field (2005) An Example of Straightforward Access to Novel Multivalent Thiosaccharides. J Org Chem, 70, pp. 7389-7396
  • Zhang, Y., Cao, R., Yin, F., Hudock, M.P., Guo, R.T., Krysiak, K., Mukherjee, S., Oldfield, E., Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: An X-ray and NMR investigation (2009) J Am Chem Soc, 131, pp. 5153-5162. , https://doi.org/10.1021/ja808285e
  • Van Dooren, G.G., Tomova, C., Agrawal, S., Humbel, B.M., Striepen, B., Toxoplasma gondii Tic20 is essential for apicoplast protein import (2008) Proc Natl Acad Sci U S A, 105, pp. 13574-13579. , https://doi.org/10.1073/pnas.0803862105
  • Berenbaum, M.C., A method for testing for synergy with any number of agents (1978) J Infect Dis, 137, pp. 122-130. , https://doi.org/10.1093/infdis/137.2.122
  • Muralidharan, V., Oksman, A., Pal, P., Lindquist, S., Goldberg, D.E., Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers (2012) Nat Commun, 3, p. 1310. , https://doi.org/10.1038/ncomms2306
  • Vinayak, S., Pawlowic, M.C., Sateriale, A., Brooks, C.F., Studstill, C.J., Bar-Peled, Y., Cipriano, M.J., Striepen, B., Genetic modification of the diarrhoeal pathogen Cryptosporidium parvum (2015) Nature, 523, pp. 477-480. , https://doi.org/10.1038/nature14651
  • Gut, J., Nelson, R.G., Cryptosporidium parvum: Synchronized excystation in vitro and evaluation of sporozoite infectivity with a new lectinbased assay (1999) J Eukaryot Microbiol, 46, pp. 56S-57S

Citas:

---------- APA ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., Striepen, B.,..., Rodriguez, J.B. (2017) . In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites. Antimicrobial Agents and Chemotherapy, 61(2).
http://dx.doi.org/10.1128/AAC.01590-16
---------- CHICAGO ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., et al. "In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites" . Antimicrobial Agents and Chemotherapy 61, no. 2 (2017).
http://dx.doi.org/10.1128/AAC.01590-16
---------- MLA ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., et al. "In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites" . Antimicrobial Agents and Chemotherapy, vol. 61, no. 2, 2017.
http://dx.doi.org/10.1128/AAC.01590-16
---------- VANCOUVER ----------
Szajnman, S.H., Galaka, T., Li, Z.-H., Li, C., Howell, N.M., Chao, M.N., et al. In Vitro and in Vivo activities of sulfur-containing linear bisphosphonates against apicomplexan parasites. Antimicrob. Agents Chemother. 2017;61(2).
http://dx.doi.org/10.1128/AAC.01590-16