Skip to main content
SpringerLink
Log in

Selective Lead Compounds against Kinetoplastid Tubulin

  • Chapter
Drug Targets in Kinetoplastid Parasites

Part of the book series: Advances In Experimental Medicine And Biology ((AEMB,volume 625))

Abstract

Kinetoplastid parasites are responsible for the potentially fatal diseases leishmaniasis, African sleeping sickness and Chagas disease. The current treatments for these diseases are far from ideal and new compounds are needed as antiparasitic drug candidates. Tubulin is the accepted target for treatments against cancer and helminths, suggesting that kinetoplastid tubulin is also a suitable target for antiprotozoal compounds. Selective lead compounds against kinetoplastid tubulin have been identified that could represent a starting point for the development of new drug candidates against these parasites.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Pellegrini F, Budman DR. Review: Tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest 2005; 23:264–273.

    Article  PubMed  CAS  Google Scholar 

  2. Zhou J, Giannakakou P. Targeting microtubules for cancer chemotherapy. Curr Med Chem-Anti-Cancer Agents 2005; 5:65–71.

    Article  CAS  Google Scholar 

  3. Martin RJ, Robertson AP, Bjorn H. Target sites of anthelmintics. Parasitol 1997; 114:S111–S124.

    Google Scholar 

  4. Nicolaou KC, Yang Z, Liu JJ. Total synthesis of taxol. Nature 1994; 367:630–634.

    Article  PubMed  CAS  Google Scholar 

  5. Srivastava V, Negi AS, Kumar JK et al. Plant-based anticancer molecules: A chemical and biological profile of some important leads. Bioorg Med Chem 2005; 13:5892–5908.

    Article  PubMed  CAS  Google Scholar 

  6. Wilson L, Miller HP, Farrell KW et al. Taxol stabilization of microtubules in vitro: Dynamics of tubulin addition and loss at opposite microtubule ends. Biochemistry 1985; 24:5254–5262.

    Article  PubMed  CAS  Google Scholar 

  7. Arregui L, Muñoz-Fontela C, Serrano S et al. Direct visualization of the microtubular cytoskeleton of ciliated protozoa with a fluorescent taxiod. J Eukaryot Microbiol 2002; 49:312–318.

    Article  PubMed  Google Scholar 

  8. Croft SL, Barrett MP, Urbina JA. Chemotheraphy of trypanosomiases and leishmaniasis. Trends Parasitol 2005; 21:508–512.

    Article  PubMed  CAS  Google Scholar 

  9. Werbovetz KA. Tubulin as an antiprotozoal drug target. Mini Rev Med Chem 2002; 2:519–529.

    Article  PubMed  CAS  Google Scholar 

  10. Downing KH, Nogales E. Tubulin structure: Insights into microtubule properties and functions. Curr Opin Struct Biol 1998; 8:785–791.

    Article  PubMed  CAS  Google Scholar 

  11. Kline-Smith SL, Walczak CE. Mitotic spindle assembly and chromosome segregation: Refocusing on microtubule dynamics. Mol Cell 2004; 15:317–327.

    Article  PubMed  CAS  Google Scholar 

  12. Amos LA, Schlieper D. Microtubules and maps. Adv Protein Chem 2005; 71:257–298.

    Article  PubMed  CAS  Google Scholar 

  13. Castoldi M, Popov AV. Purification of brain tubulin through two cycles of polymerizationdepolymerization in a high-molarity buffer. Protein Expr Purif 2003; 32:83–88.

    Article  PubMed  CAS  Google Scholar 

  14. Fourest-Lieuvin A. Purification of tubulin from limited volumes of cultured cells. Protein Expr Purif 2006; 45:183–190.

    Article  PubMed  CAS  Google Scholar 

  15. Werbovetz KA, Brendle JJ, Sackett DL. Purification, characterisation and drug susceptibility of tubulin from Leishmania. Mol Biochem Parasitol 1999; 98:53–65.

    Article  PubMed  CAS  Google Scholar 

  16. Gull K. Protist tubulins: New arrivals, evolutionary relationships and insights to cytoskeletal function. Curr Opin Microbiol 2001; 4:427–432.

    Article  PubMed  CAS  Google Scholar 

  17. Hu K, Roos DS, Murray JM. A novel polymer of tubulin forms the conoid of Toxoplasma gondii. J Cell Biol 2002; 156:139–1050.

    Article  Google Scholar 

  18. Kohl L, Gull K. Molecular architecture of the trypanosome cytoskeleton. Mol Biochem Parasitol 1998; 93:1–9.

    Article  PubMed  CAS  Google Scholar 

  19. Lubega GW, Ochola OK, Prichard RK. Trypanosoma brucci: Anti-tubulin antibodies specifically inhibit trypanosome growth in culture. Exp Parasitol 2002; 102:134–142.

    Article  PubMed  CAS  Google Scholar 

  20. Rao S, Krauss NE, Heerding JM et al. 3'-(p-Azidobenzamido)taxol photolabels the N-terminal 31 amino acids of β-tubulin. J Biol Chem 1994; 269:3132–3134.

    PubMed  CAS  Google Scholar 

  21. Rao S, Orr GA, Chaudhary AG et al. Characterization of the taxol binding site on the microtubule. 2-(m-Azido benzoyl)taxol photolabels a peptide (amino acids 217-231) of tubulin. J Biol Chem 1995; 270:20235–20238.

    Article  PubMed  CAS  Google Scholar 

  22. Nogales E, Wolf SG, Downing KH. Structure of the αβ tubulin dimer by electron crystallography. Nature 1998; 391:199–203.

    Article  PubMed  CAS  Google Scholar 

  23. Löwe J, Li H, Downing KH et al. Refined structure of αβ-tubulin at 3.5 Å resolution. J Mol Biol 2001; 313:1045–1057.

    Article  PubMed  Google Scholar 

  24. Bollag DM, McQueney PA, Zhu J et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 1995; 55:2325–2333.

    PubMed  CAS  Google Scholar 

  25. Giannakakou P, Gussio R, Nogales E. A common pharmacophore for epothilone and taxanes: Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc Natl Acad Sci USA 2000; 97:2904–2909.

    Article  PubMed  CAS  Google Scholar 

  26. Long BH, Carboni JM, Wasserman AJ et al. Eleutherobin, a novel cytotoxic agent that induces tubulin polymerisation, is similar to paclitaxel (taxol). Cancer Res 1998; 58:1111–1115.

    PubMed  CAS  Google Scholar 

  27. Jiménez-Barbero J, Amat-Guerri F, Snyder JP. The solid state, solution and tubulin-bound conformations of agents that promote microtubule stabilization. Curr Med Chem-Anti-Cancer Agents 2002; 2:91–122.

    Article  Google Scholar 

  28. Havens CG, Bryant N, Asher L et al. Cellular effects of leishmanial tubulin inhibitors on L. donovani. Mol Biochem Parasitol 2000; 110:223–236.

    Article  PubMed  CAS  Google Scholar 

  29. Baum SG, Wittner M, Nadler JP. Taxol, a microtubule stablizing agent, blocks the replication of Trypanosoma cruzi. Proc Natl Acad Sci 1981; 78:4571–4575.

    Article  PubMed  CAS  Google Scholar 

  30. Moulay L, Robert-Gero M, Brown S et al. Sinefungin and taxol effects on cell cycle and cytoskeleton of Leishmania donovani promastigotes. Exp Cell Res 1996; 226:283–291.

    Article  PubMed  CAS  Google Scholar 

  31. Kapoor P, Sachdeva M, Madhubala R. Effect of the microtubule stablising agent taxol on leishmanial protozoan parasites in vitro. FEMS Microbiol Lett 1999; 176:429–435.

    Article  PubMed  CAS  Google Scholar 

  32. Dantas AP, Barbosa HS, De Castro SL. Biological and ultrastructural effects of the anti-microtubule agent taxol against Trypanosoma cruzi. J Submicrosc Cytol Pathol 2003; 35:287–294.

    PubMed  CAS  Google Scholar 

  33. Luduena RF, Roach MC. Tubulin sulfhydryl groups as probes and targets for anitmitotic and antimicrotubule agents. Pharmacol Ther 1991; 49:133–152.

    Article  PubMed  Google Scholar 

  34. Rai S, Wolff J. Localization of the vinblastine-binding site on β-tubulin. J Biol Chem 1996; 271:14707–14711.

    Article  PubMed  CAS  Google Scholar 

  35. Chatterjee SK, Laffray J, Patel P et al. Interaction of tubulin with a new fluorescent analogue of vinblastine. Biochemistry 2002; 41:14010–14018.

    Article  PubMed  CAS  Google Scholar 

  36. Gigant B, Wang C, Ravelli RBG et al. Structural basis for the regulation of tubulin by vinblastine. Nature 2005; 435:519–522.

    Article  PubMed  CAS  Google Scholar 

  37. Grellier P, Sinou V, Garreau-de Loubresse N et al. Selective and reversible effects of vinca alkaloids on Trypanosoma cruzi epimastigote forms: Blockage of cytokinesis without inhibition of the organelle duplication. Cell Motil Cytoskeleton 1999; 42:36–47.

    Article  PubMed  CAS  Google Scholar 

  38. Ochola, DO, Prichard RK, Lubega GW. Classical ligands bind tubulin of trypanosomes and inhibit their growth in vitro. J Parasitol 2002; 88:600–604.

    PubMed  CAS  Google Scholar 

  39. Floyd LJ, Barnes LD, Williams RF. Photoaffinity labelling of tubulin with (2-nitro-4-azidophenyl) deacetylcolchicine: Direct evidence for two colchicine binding sites. Biochemistry 1989; 28:8515–8525.

    Article  PubMed  CAS  Google Scholar 

  40. Uppuluri S, Knipling L, Sackett DL et al. Localization of the colchicine-binding site of tubulin. Proc Natl Acad Sci USA 1993; 90:11598–11602.

    Article  PubMed  CAS  Google Scholar 

  41. Bai R, Pei XF, Boyé O et al. Identification of cysteine 354 of β-tubulin as part of the binding site for the A ring of colchicine. J Biol Chem 1996; 271:12639–12645.

    Article  PubMed  CAS  Google Scholar 

  42. Ruoli B, Covell DG, Pei XF et al. Mapping the binding site of colchicinoids on β-tubulin. 2-Chloroacetyl-2-demethylthiocolchicine covalently reacts predominantly with cysteine 239 and secondary with cysteine 354. J Biol Chem 2000; 275:40443–40452.

    Article  Google Scholar 

  43. Ravell RBG, Gigant B, Curmi PA et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 2004; 428:198–202.

    Article  Google Scholar 

  44. Shearwin KE, Timasheff SN. Effect of cochicine analogues on the dissociation of αβ tubulin into subunits: The locus of colchicine binding. Biochemistry 1994; 33:894–901.

    Article  PubMed  CAS  Google Scholar 

  45. Burns RG. Analysis of the colchicine-binding site of β-tubulin. FEBS Lett 1992; 297:205–208.

    Article  PubMed  CAS  Google Scholar 

  46. Macrae TH, Gull K. Purification and assembly in vitro of tubulin from Trypanosoma brucei brucei. Biochem J 1990; 265:87–93.

    PubMed  CAS  Google Scholar 

  47. MacDonald LM, Armson A, Thompson RCA et al. Characterization of factors favouring the expression of soluble protozoan tubulin proteins in Escherichia coli. Protein Expr Purif 2003; 29:117–122.

    Article  PubMed  CAS  Google Scholar 

  48. Russell DG, Miller D, Gull K. Tubulin heterogeneity in the trypanosome Crithidia fasciculata. Mol Cell Biol 1984; 4:779–790.

    PubMed  CAS  Google Scholar 

  49. Yakovich AJ, Ragone FL, Alfonzo JD et al. Leishmania tarentolae: Purification and characterization of tubulin and its suitability as a substrate for antileishmanial drug screening. Exp Parasitol 2006; in press.

    Google Scholar 

  50. Wenyon D. Observations on the intestinal protozoa of three Egyptian lizards, with a note on a cell-invading fungus. Parasitol 1921; 12:133–140.

    Google Scholar 

  51. Chan MMY, Fong D. Inhibition of leishmanias but not host macrophages by the antitubulin herbicide trifluralin. Science 1990; 249:924–926.

    Article  PubMed  CAS  Google Scholar 

  52. Traub-Cseko YM, Ramalho-Ortgao JM, Dantas AP et al. Dintroaniline herbicides against protozoan parasites; the case of Trpanosoma cruzi. Trends Parasitol 2001; 17:136–141.

    Article  PubMed  CAS  Google Scholar 

  53. Chan MMY, Grogl M, Chen CC et al. Herbicides to curb human parasitic infections: In vitro and in vivo effects of trifluralin on the trypanosomatid protozoans. Proc Natl Acad Sci USA 1993; 90:5657–5661.

    Article  PubMed  CAS  Google Scholar 

  54. Callahan HL, Kelley C, Pereira T et al. Microtubule inhibitors: Structure-activity analyses suggest rational models to identify potentially active compounds. Antimicrob Agents Chemother 1996; 40:947–952.

    PubMed  CAS  Google Scholar 

  55. Morejohn LC, Fosket DE. The biochemistry of compounds with anti-microtubule activity in plant cells. Pharmacol Ther 1991; 51:217–230.

    Article  PubMed  CAS  Google Scholar 

  56. Bhattacharya G, Salem MM, Werbovetz KA. Anitleishmanial dinitroaniline sulfonamides with activity against parasite tubulin. Bioorg Med Chem Lett 2002; 21:2395–2398.

    Article  Google Scholar 

  57. Bhattacharya G, Herman J, Delffn D et al. Synthesis and antitubulin activity of N1-and N4-substituted 3,5-dinitro sulfanilamides against African Trypanosomes and Leishmania. J Med Chem 2004; 47:1823–1832.

    Article  PubMed  CAS  Google Scholar 

  58. Werbovetz KA, Sackett DL, Delffn D et al. Selective antimicrotubule activity of N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5) against kinetoplastid parasites. Mol Pharmacol 2003; 64:1325–1333.

    Article  PubMed  CAS  Google Scholar 

  59. Wu D, George TG, Hurh E et al. Presystemic metabolism prevents in vivo antikinetoplastid activity of N1, N4-substituted 3,5-dinitro sulfanilamide, GB-II-150. Life Sci 2006; 79:1081–1093.

    Article  PubMed  CAS  Google Scholar 

  60. George TG, Johnsamuel J, Delffn DA et al. Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides. Bioorg Med Chem 2006; 14:5699–5710.

    Article  PubMed  CAS  Google Scholar 

  61. Morrissette NS, Mitra A, Sept D et al. Dinitroanilines bind a-tubulin to disrupt microtubules. Mol Biol Cell 2004; 25:1960–1968.

    Article  Google Scholar 

  62. Abraham I, Dion RL, Duanmu et al. 2,4-Dichlorobenzyl thiocyante, an antimitotic agent that alters microtubule morphology. Proc Natl Acad Sci USA 1986; 83:6839–6843.

    Article  PubMed  CAS  Google Scholar 

  63. Bai RL, Lin CM, Nguyen NY et al. Identification of the cysteine residue of β-tubulin alkylated by the antimitotic agent 2,4-dichlorobenyzl thiocyante, facilitated by separation of the protein sub-units of tubulin by hydrophobic column chromatography. Biochem 1989; 28:5606–5612.

    Article  CAS  Google Scholar 

  64. Szajnman SH, Yan W, Bailey BN et al. Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation. J Med Chem 2000; 43:1826–1840.

    Article  PubMed  CAS  Google Scholar 

  65. Cottrell DM, Capers J, Salem MM et al. Antikinetoplastid activity of 3-aryl-5-thiocy-anatomethyl-l, 2,4-oxadiazoles. Bioorg Med Chem 2004; 12:2815–2824.

    Article  PubMed  CAS  Google Scholar 

  66. Abraham I, Dion RL, Duanmu C et al. 2,4-Dichlorobenzyl thiocyanate, an antimitotic agent that alters microtubule morphology. Proc Natl Acad Sci USA 1986; 83:6839–6943.

    Article  PubMed  CAS  Google Scholar 

  67. Morgan RE, Westwood NJ. Screening and synthesis: High throughput technologies applied to parasitology. Parasitol 2004; 128:SS71–S79.

    Google Scholar 

  68. Baldwin J, Michnoff CH, Malmquist NA et al. High-throughput screening for potent and selective inhibitors of Plasmoduim falciparum dihydroorotate dehydrogenase. J Biol Chem 2005; 280:21847–21853.

    Article  PubMed  CAS  Google Scholar 

  69. St. George S, Bishop JV, Titus RG et al. Novel compounds active against Leishmania major. Antimicrob Agents Chemother 2006; 50:474–479.

    Article  Google Scholar 

  70. Haggarty SJ, Mayer TU, Miyamoto et al. Dissecting cellular processes using small molecules: Identification of colchincine-like, taxol-like and other small molecules that perturb mitosis. Chem Biol 2000; 7:275–286.

    Article  PubMed  CAS  Google Scholar 

  71. Mayer TU, Kapoor TM, Haggarty SJ et al. Small molecule inhibitors of mitotic spindle bipolarity identified in a phenotype-based screen. Science 1999; 286:971–974.

    Article  PubMed  CAS  Google Scholar 

  72. Hamel E, Blokhin AV, Dale G et al. Limitations in the use of tubulin polymerization assays as a screen for the identification of new antimitotic agents: The potent marine natural product curacin A as an example. Drug Dev Res 1995; 34:110–120.

    Article  CAS  Google Scholar 

  73. Kokoshka JM, Ireland CM, Barrows LR. Cell-based screen for identification of inhibitors of tubulin polymerization. J Nat Prod 1996; 59:1179–182.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Medicinal Chemistry and Pharmacognosy College of Pharmacy, The Ohio State University Columbus, Ohio, USA

    R.E. Morgan

  2. Division of Medicinal Chemistry and Pharmacognosy College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA

    K.A. Werbovetz*

Authors
  1. R.E. Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K.A. Werbovetz*
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, Kolkata, India

    Hemanta K. Majumder

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Morgan, R., Werbovetz*, K. (2008). Selective Lead Compounds against Kinetoplastid Tubulin. In: Majumder, H.K. (eds) Drug Targets in Kinetoplastid Parasites. Advances In Experimental Medicine And Biology, vol 625. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77570-8_4

Download citation

Publish with us

Policies and ethics

Search

Navigation