Skip to main content

Advertisement

SpringerLink
Log in

Drug targets in Leishmania

  • Review Article
  • Published:
Journal of Parasitic Diseases Aims and scope Submit manuscript

Abstract

Leishmaniasis is a major public health problem and till date there are no effective vaccines available. The control strategy relies solely on chemotherapy of the infected people. However, the present repertoire of drugs is limited and increasing resistance towards them has posed a major concern. The first step in drug discovery is to identify a suitable drug target. The genome sequences of Leishmania major and Leishmania infantum has revealed immense amount of information and has given the opportunity to identify novel drug targets that are unique to these parasites. Utilization of this information in order to come up with a candidate drug molecule requires combining all the technology and using a multi-disciplinary approach, right from characterizing the target protein to high throughput screening of compounds. Leishmania belonging to the order kinetoplastidae emerges from the ancient eukaryotic lineages. They are quite diverse from their mammalian hosts and there are several cellular processes that we are getting to know of, which exist distinctly in these parasites. In this review, we discuss some of the metabolic pathways that are essential and could be used as potential drug targets in Leishmania.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Abbruzzese A, Park MH, Folk JE (1986) Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. J Biol Chem 261:3085–3089

    CAS  PubMed  Google Scholar 

  • Alexander J, Coombs GH, Mottram JC (1998) Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response. J Immunol 161:6794–6801

    CAS  PubMed  Google Scholar 

  • Aronov AM, Suresh S, Buckner FS, Van Voorhis WC, Verlinde CL, Opperdoes FR, Hol WG, Gelb MH (1999) Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci USA 96:4273–4278

    Article  CAS  PubMed  Google Scholar 

  • Barrett MP, Mottram JC, Coombs GH (1999) Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. Trends Microbiol 7:82–88

    Article  CAS  PubMed  Google Scholar 

  • Bengs F, Scholz A, Kuhn D, Wiese M (2005) LmxMPK9, a mitogen-activated protein kinase homologue affects flagellar length in Leishmania mexicana. Mol Microbiol 55:1606–1615

    Article  CAS  PubMed  Google Scholar 

  • Bernstein BE, Michels PA, Hol WG (1997) Synergistic effects of substrate-induced conformational changes in phosphoglycerate kinase activation. Nature 385:275–278

    Article  CAS  PubMed  Google Scholar 

  • Bodley AL, Wani MC, Wall ME, Shapiro TA (1995) Antitrypanosomal activity of camptothecin analogs. Structure–activity correlations. Biochem Pharmacol 50:937–942

    Article  CAS  PubMed  Google Scholar 

  • Bryson K, Besteiro S, McGachy HA, Coombs GH, Mottram JC, Alexander J (2009) Overexpression of the natural inhibitor of cysteine peptidases in Leishmania mexicana leads to reduced virulence and a Th1 response. Infect Immun 77:2971–2978

    Article  CAS  PubMed  Google Scholar 

  • Carter NS, Drew ME, Sanchez M, Vasudevan G, Landfear SM, Ullman B (2000) Cloning of a novel inosine-guanosine transporter gene from Leishmania donovani by functional rescue of a transport-deficient mutant. J Biol Chem 275:20935–20941

    Article  CAS  PubMed  Google Scholar 

  • Chauhan SC, Madhubala R (2009) Glyoxalase I gene deletion mutants of Leishmania donovani exhibit reduced methylglyoxal detoxification. PLoS.One. 4:e6805

    Article  PubMed  Google Scholar 

  • Chawla B, Jhingran A, Singh S, Tyagi N, Park MH, Srinivasan N, Roberts SC, Madhubala R (2010) Identification and characterization of a novel deoxyhypusine synthase in Leishmania donovani. J Biol Chem 285:453–463

    Article  CAS  PubMed  Google Scholar 

  • Chen KY, Dou QP (1988) NAD+ stimulated the spermidine-dependent hypusine formation on the 18 kDa protein in cytosolic lysates derived from NB-15 mouse neuroblastoma cells. FEBS Lett 229:325–328

    Article  CAS  PubMed  Google Scholar 

  • Chowdhury AR, Mandal S, Goswami A, Ghosh M, Mandal L, Chakraborty D, Ganguly A, Tripathi G, Mukhopadhyay S, Bandyopadhyay S, Majumder HK (2003) Dihydrobetulinic acid induces apoptosis in Leishmania donovani by targeting DNA topoisomerase I and II: implications in antileishmanial therapy. Mol Med 9:26–36

    CAS  PubMed  Google Scholar 

  • Chudzik DM, Michels PA, de WS, Hol WG (2000) Structures of type 2 peroxisomal targeting signals in two trypanosomatid aldolases. J Mol Biol 300:697–707

    Article  CAS  PubMed  Google Scholar 

  • Cooper RA (1984) Metabolism of methylglyoxal in microorganisms. Annu Rev Microbiol 38:49–68

    Article  CAS  PubMed  Google Scholar 

  • Das A, Dasgupta A, Sharma S, Ghosh M, Sengupta T, Bandopadhyay S, Majumder HK (2001) Characterisation of the gene encoding type II DNA topoisomerase from Leishmania donovani: a key molecular target in antileishmanial therapy. Nucleic Acids Res 29:1844–1851

    Article  CAS  PubMed  Google Scholar 

  • Das A, Dasgupta A, Sengupta T, Majumder HK (2004a) Topoisomerases of kinetoplastid parasites as potential chemotherapeutic targets. Trends Parasitol 20:381–387

    Article  CAS  PubMed  Google Scholar 

  • Das BB, Sen N, Ganguly A, Majumder HK (2004b) Reconstitution and functional characterization of the unusual bi-subunit type I DNA topoisomerase from Leishmania donovani. FEBS Lett 565:81–88

    Article  CAS  PubMed  Google Scholar 

  • Davies DR, Mushtaq A, Interthal H, Champoux JJ, Hol WG (2006) The structure of the transition state of the heterodimeric topoisomerase I of Leishmania donovani as a vanadate complex with nicked DNA. J Mol Biol 357:1202–1210

    Article  CAS  PubMed  Google Scholar 

  • Docampo R, Moreno SN (2008) The acidocalcisome as a target for chemotherapeutic agents in protozoan parasites. Curr Pharm Des 14:882–888

    Article  CAS  PubMed  Google Scholar 

  • Dumas C, Ouellette M, Tovar J, Cunningham ML, Fairlamb AH, Tamar S, Olivier M, Papadopoulou B (1997) Disruption of the trypanothione reductase gene of Leishmania decreases its ability to survive oxidative stress in macrophages. EMBO J 16:2590–2598

    Article  CAS  PubMed  Google Scholar 

  • Fairlamb AH, Blackburn P, Ulrich P, Chait BT, Cerami A (1985) Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. Science 227:1485–1487

    Article  CAS  PubMed  Google Scholar 

  • Ferguson MA (2000) Glycosylphosphatidylinositol biosynthesis validated as a drug target for African sleeping sickness. Proc Natl Acad Sci USA 97:10673–10675

    Article  CAS  PubMed  Google Scholar 

  • Ferguson MA, Brimacombe JS, Brown JR, Crossman A, Dix A, Field RA, Guther ML, Milne KG, Sharma DK, Smith TK (1999) The GPI biosynthetic pathway as a therapeutic target for African sleeping sickness. Biochim Biophys Acta 1455:327–340

    CAS  PubMed  Google Scholar 

  • Fernandes Rodrigues JC, Concepcion JL, Rodrigues C, Caldera A, Urbina JA, de Souza W (2008) In vitro activities of ER-119884 and E5700, two potent squalene synthase inhibitors, against Leishmania amazonensis: antiproliferative, biochemical, and ultrastructural effects. Antimicrob Agents Chemother 52:4098–4114

    Article  PubMed  Google Scholar 

  • Figgitt D, Denny W, Chavalitshewinkoon P, Wilairat P, Ralph R (1992) In vitro study of anticancer acridines as potential antitrypanosomal and antimalarial agents. Antimicrob Agents Chemother 36:1644–1647

    CAS  PubMed  Google Scholar 

  • Fish WR, Marr JJ, Berens RL, Looker DL, Nelson DJ, LaFon SW, Balber AE (1985) Inosine analogs as chemotherapeutic agents for African trypanosomes: metabolism in trypanosomes and efficacy in tissue culture. Antimicrob Agents Chemother 27:33–36

    CAS  PubMed  Google Scholar 

  • Fragoso SP, Goldenberg S (1992) Cloning and characterization of the gene encoding Trypanosoma cruzi DNA topoisomerase II. Mol Biochem Parasitol 55:127–134

    Article  CAS  PubMed  Google Scholar 

  • Galazka J, Carter NS, Bekhouche S, Arastu-Kapur S, Ullman B (2006) Point mutations within the LdNT2 nucleoside transporter gene from Leishmania donovani confer drug resistance and transport deficiency. Int J Biochem Cell Biol 38:1221–1229

    Article  CAS  PubMed  Google Scholar 

  • Glew RH, Saha AK, Das S, Remaley AT (1988) Biochemistry of the Leishmania species. Microbiol Rev 52:412–432

    CAS  PubMed  Google Scholar 

  • Grant KM, Hassan P, Anderson JS, Mottram JC (1998) The crk3 gene of Leishmania mexicana encodes a stage-regulated cdc2-related histone H1 kinase that associates with p12. J Biol Chem 273:10153–10159

    Article  CAS  PubMed  Google Scholar 

  • Grant KM, Dunion MH, Yardley V, Skaltsounis AL, Marko D, Eisenbrand G, Croft SL, Meijer L, Mottram JC (2004) Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase: chemical library screen and antileishmanial activity. Antimicrob Agents Chemother 48:3033–3042

    Article  CAS  PubMed  Google Scholar 

  • Guther ML, Masterson WJ, Ferguson MA (1994) The effects of phenylmethylsulfonyl fluoride on inositol-acylation and fatty acid remodeling in African trypanosomes. J Biol Chem 269:18694–18701

    CAS  PubMed  Google Scholar 

  • Hardy LW, Matthews W, Nare B, Beverley SM (1997) Biochemical and genetic tests for inhibitors of Leishmania pteridine pathways. Exp Parasitol 87:157–169

    Article  CAS  PubMed  Google Scholar 

  • Hassan P, Fergusson D, Grant KM, Mottram JC (2001) The CRK3 protein kinase is essential for cell cycle progression of Leishmania mexicana. Mol Biochem Parasitol 113:189–198

    Article  CAS  PubMed  Google Scholar 

  • Irsch T, Krauth-Siegel RL (2004) Glyoxalase II of African trypanosomes is trypanothione-dependent. J Biol Chem 279:22209–22217

    Article  CAS  PubMed  Google Scholar 

  • Ishida K, Rodrigues JC, Ribeiro MD, Vila TV, de SW, Urbina JA, Nakamura CV, Rozental S (2009) Growth inhibition and ultrastructural alterations induced by Delta24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms. BMC Microbiol 9:74

    Article  PubMed  Google Scholar 

  • Ivens AC, Peacock CS, Worthey EA, Murphy L, Aggarwal G, Berriman M, Sisk E, Rajandream MA, Adlem E, Aert R, Anupama A, Apostolou Z, Attipoe P, Bason N, Bauser C, Beck A, Beverley SM, Bianchettin G, Borzym K, Bothe G, Bruschi CV, Collins M, Cadag E, Ciarloni L, Clayton C, Coulson RM, Cronin A, Cruz AK, Davies RM, De GJ, Dobson DE, Duesterhoeft A, Fazelina G, Fosker N, Frasch AC, Fraser A, Fuchs M, Gabel C, Goble A, Goffeau A, Harris D, Hertz-Fowler C, Hilbert H, Horn D, Huang Y, Klages S, Knights A, Kube M, Larke N, Litvin L, Lord A, Louie T, Marra M, Masuy D, Matthews K, Michaeli S, Mottram JC, Muller-Auer S, Munden H, Nelson S, Norbertczak H, Oliver K, O’neil S, Pentony M, Pohl TM, Price C, Purnelle B, Quail MA, Rabbinowitsch E, Reinhardt R, Rieger M, Rinta J, Robben J, Robertson L, Ruiz JC, Rutter S, Saunders D, Schafer M, Schein J, Schwartz DC, Seeger K, Seyler A, Sharp S, Shin H, Sivam D, Squares R, Squares S, Tosato V, Vogt C, Volckaert G, Wambutt R, Warren T, Wedler H, Woodward J, Zhou S, Zimmermann W, Smith DF, Blackwell JM, Stuart KD, Barrell B, Myler PJ (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 309:436–442

    Article  PubMed  Google Scholar 

  • Kager PA, Rees PH, Wellde BT, Hockmeyer WT, Lyerly WH (1981) Allopurinol in the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg 75:556–559

    Article  CAS  PubMed  Google Scholar 

  • Kerr ID, Wu P, Marion-Tsukamaki R, Mackey ZB, Brinen LS (2010) Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei. PLoS Negl Trop Dis 4:e701

    Article  PubMed  Google Scholar 

  • Kim H, Feil IK, Verlinde CL, Petra PH, Hol WG (1995) Crystal structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Leishmania mexicana: implications for structure-based drug design and a new position for the inorganic phosphate binding site. Biochemistry 34:14975–14986

    Article  CAS  PubMed  Google Scholar 

  • Lorente SO, Rodrigues JC, Jimenez JC, Joyce-Menekse M, Rodrigues C, Croft SL, Yardley V, de Luca-Fradley K, Ruiz-Perez LM, Urbina J, de Souza W, Gonzalez PD, Gilbert IH (2004) Novel azasterols as potential agents for treatment of leishmaniasis and trypanosomiasis. Antimicrob Agents Chemother 48:2937–2950

    Article  PubMed  Google Scholar 

  • Mackey ZB, O’Brien TC, Greenbaum DC, Blank RB, McKerrow JH (2004) A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei. J Biol Chem 279:48426–48433

    Article  CAS  PubMed  Google Scholar 

  • Magaraci F, Jimenez CJ, Rodrigues C, Rodrigues JC, Braga MV, Yardley V, de Luca-Fradley K, Croft SL, de Souza W, Ruiz-Perez LM, Urbina J, Gonzalez PD, Gilbert IH (2003) Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi. J.Med.Chem. 46:4714–4727

    Article  CAS  PubMed  Google Scholar 

  • Marr JJ (1983) Pyrazolopyrimidine metabolism in Leishmania and trypanosomes: significant differences between host and parasite. J Cell Biochem 22:187–196

    Article  CAS  PubMed  Google Scholar 

  • Martin MB, Grimley JS, Lewis JC, Heath HT III, Bailey BN, Kendrick H, Yardley V, Caldera A, Lira R, Urbina JA, Moreno SN, Docampo R, Croft SL, Oldfield E (2001) Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy. J Med Chem 44:909–916

    Article  CAS  PubMed  Google Scholar 

  • Martinez S, Marr JJ (1992) Allopurinol in the treatment of American cutaneous leishmaniasis. N Engl J Med 326:741–744

    Article  CAS  PubMed  Google Scholar 

  • Murphey RJ, Gerner EW (1987) Hypusine formation in protein by a two-step process in cell lysates. J Biol Chem 262:15033–15036

    CAS  PubMed  Google Scholar 

  • Myler PJ (2008) Searching the Tritryp genomes for drug targets. Adv Exp Med Biol 625:133–140

    Article  CAS  PubMed  Google Scholar 

  • Nare B, Luba J, Hardy LW, Beverley S (1997) New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity. Parasitology 114(Suppl):S101–S110

    PubMed  Google Scholar 

  • Neal RA, Croft SL (1984) An in vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani. J Antimicrob Chemother 14:463–475

    Article  CAS  PubMed  Google Scholar 

  • Nishimura K, Murozumi K, Shirahata A, Park MH, Kashiwagi K, Igarashi K (2005) Independent roles of eIF5A and polyamines in cell proliferation. Biochem J 385:779–785

    Article  CAS  PubMed  Google Scholar 

  • O’Brien TC, Mackey ZB, Fetter RD, Choe Y, O’Donoghue AJ, Zhou M, Craik CS, Caffrey CR, McKerrow JH (2008) A parasite cysteine protease is key to host protein degradation and iron acquisition. J Biol Chem 283:28934–28943

    Article  PubMed  Google Scholar 

  • Opperdoes FR (1987) Compartmentation of carbohydrate metabolism in trypanosomes. Annu Rev Microbiol 41:127–151

    Article  CAS  PubMed  Google Scholar 

  • Ortiz D, Sanchez MA, Koch HP, Larsson HP, Landfear SM (2009) An acid-activated nucleobase transporter from Leishmania major. J Biol Chem 284:16164–16169

    Article  CAS  PubMed  Google Scholar 

  • Padmanabhan PK, Mukherjee A, Singh S, Chattopadhyaya S, Gowri VS, Myler PJ, Srinivasan N, Madhubala R (2005) Glyoxalase I from Leishmania donovani: a potential target for anti-parasite drug. Biochem Biophys Res Commun 337:1237–1248

    Article  CAS  PubMed  Google Scholar 

  • Padmanabhan PK, Mukherjee A, Madhubala R (2006) Characterization of the gene encoding glyoxalase II from Leishmania donovani: a potential target for anti-parasite drugs. Biochem J 393:227–234

    Article  CAS  PubMed  Google Scholar 

  • Park MH, Cooper HL, Folk JE (1982) The biosynthesis of protein-bound hypusine (N epsilon-(4-amino-2-hydroxybutyl)lysine). Lysine as the amino acid precursor and the intermediate role of deoxyhypusine (N epsilon-(4-aminobutyl)lysine). J Biol Chem 257:7217–7222

    CAS  PubMed  Google Scholar 

  • Park MH, Wolff EC, Lee YB, Folk JE (1994) Antiproliferative effects of inhibitors of deoxyhypusine synthase. Inhibition of growth of Chinese hamster ovary cells by guanyl diamines. J Biol Chem 269:27827–27832

    CAS  PubMed  Google Scholar 

  • Park MH, Joe YA, Kang KR (1998) Deoxyhypusine synthase activity is essential for cell viability in the yeast Saccharomyces cerevisiae. J Biol Chem 273:1677–1683

    Article  CAS  PubMed  Google Scholar 

  • Pink R, Hudson A, Mouries MA, Bendig M (2005) Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov 4:727–740

    Article  CAS  PubMed  Google Scholar 

  • Rigden DJ, Phillips SE, Michels PA, Fothergill-Gilmore LA (1999) The structure of pyruvate kinase from Leishmania mexicana reveals details of the allosteric transition and unusual effector specificity. J Mol Biol 291:615–635

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues JC, Attias M, Rodriguez C, Urbina JA, Souza W (2002) Ultrastructural and biochemical alterations induced by 22,26-azasterol, a delta(24(25))-sterol methyltransferase inhibitor, on promastigote and amastigote forms of Leishmania amazonensis. Antimicrob Agents Chemother 46:487–499

    Article  CAS  PubMed  Google Scholar 

  • Sacks DL, Modi G, Rowton E, Spath G, Epstein L, Turco SJ, Beverley SM (2000) The role of phosphoglycans in Leishmania–sand fly interactions. Proc Natl Acad Sci USA 97:406–411

    Article  CAS  PubMed  Google Scholar 

  • Salem MM, Werbovetz KA (2005) Antiprotozoal compounds from Psorothamnus polydenius. J Nat Prod 68:108–111

    Article  CAS  PubMed  Google Scholar 

  • Schnier J, Schwelberger HG, Smit-McBride Z, Kang HA, Hershey JW (1991) Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol Cell Biol 11:3105–3114

    CAS  PubMed  Google Scholar 

  • Scory S, Stierhof YD, Caffrey CR, Steverding D (2007) The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo. Kinetoplastid Biol Dis 6:2

    Article  PubMed  Google Scholar 

  • Sharma DK, Smith TK, Crossman A, Brimacombe JS, Ferguson MA (1997) Substrate specificity of the N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase of glycosylphosphatidylinositol membrane anchor biosynthesis in African trypanosomes and human cells. Biochem J 328(Pt 1):171–177

    CAS  PubMed  Google Scholar 

  • Shiba T, Mizote H, Kaneko T, Nakajima T, Kakimoto Y (1971) Hypusine, a new amino acid occurring in bovine brain. Isolation and structural determination. Biochim Biophys Acta 244:523–531

    CAS  PubMed  Google Scholar 

  • Smith TK, Sharma DK, Crossman A, Dix A, Brimacombe JS, Ferguson MA (1997) Parasite and mammalian GPI biosynthetic pathways can be distinguished using synthetic substrate analogues. EMBO J 16:6667–6675

    Article  CAS  PubMed  Google Scholar 

  • Smith TK, Sharma DK, Crossman A, Brimacombe JS, Ferguson MA (1999) Selective inhibitors of the glycosylphosphatidylinositol biosynthetic pathway of Trypanosoma brucei. EMBO J 18:5922–5930

    Article  CAS  PubMed  Google Scholar 

  • Smith TK, Crossman A, Borissow CN, Paterson MJ, Dix A, Brimacombe JS, Ferguson MA (2001) Specificity of GlcNAc-PI de-N-acetylase of GPI biosynthesis and synthesis of parasite-specific suicide substrate inhibitors. EMBO J 20:3322–3332

    Article  CAS  PubMed  Google Scholar 

  • Somoza JR, Skillman AG Jr, Munagala NR, Oshiro CM, Knegtel RM, Mpoke S, Fletterick RJ, Kuntz ID, Wang CC (1998) Rational design of novel antimicrobials: blocking purine salvage in a parasitic protozoan. Biochemistry 37:5344–5348

    Article  CAS  PubMed  Google Scholar 

  • Spath GF, Epstein L, Leader B, Singer SM, Avila HA, Turco SJ, Beverley SM (2000) Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. Proc Natl Acad Sci USA 97:9258–9263

    Article  CAS  PubMed  Google Scholar 

  • Strauss PR, Wang JC (1990) The TOP2 gene of Trypanosoma brucei: a single-copy gene that shares extensive homology with other TOP2 genes encoding eukaryotic DNA topoisomerase II. Mol Biochem Parasitol 38:141–150

    Article  CAS  PubMed  Google Scholar 

  • Suresh S, Turley S, Opperdoes FR, Michels PA, Hol WG (2000) A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana. Structure 8:541–552

    Article  CAS  PubMed  Google Scholar 

  • Urbaniak MD, Crossman A, Chang T, Smith TK, van Aalten DM, Ferguson MA (2005) The N-acetyl-d-glucosaminylphosphatidylinositol De-N-acetylase of glycosylphosphatidylinositol biosynthesis is a zinc metalloenzyme. J Biol Chem 280:22831–22838

    Article  CAS  PubMed  Google Scholar 

  • Urbaniak MD, Yashunsky DV, Crossman A, Nikolaev AV, Ferguson MA (2008) Probing enzymes late in the trypanosomal glycosylphosphatidylinositol biosynthetic pathway with synthetic glycosylphosphatidylinositol analogues. ACS Chem Biol 3:625–634

    Article  CAS  PubMed  Google Scholar 

  • Urbina JA, Concepcion JL, Caldera A, Payares G, Sanoja C, Otomo T, Hiyoshi H (2004) In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrob Agents Chemother 48:2379–2387

    Article  CAS  PubMed  Google Scholar 

  • Vannier-Santos MA, Urbina JA, Martiny A, Neves A, de SW (1995) Alterations induced by the antifungal compounds ketoconazole and terbinafine in Leishmania. J Eukaryot Microbiol 42:337–346

    Article  CAS  PubMed  Google Scholar 

  • Vasudevan G, Carter NS, Drew ME, Beverley SM, Sanchez MA, Seyfang A, Ullman B, Landfear SM (1998) Cloning of Leishmania nucleoside transporter genes by rescue of a transport-deficient mutant. Proc Natl Acad Sci USA 95:9873–9878

    Article  CAS  PubMed  Google Scholar 

  • Vasudevan G, Ullman B, Landfear SM (2001) Point mutations in a nucleoside transporter gene from Leishmania donovani confer drug resistance and alter substrate selectivity. Proc Natl Acad Sci USA 98:6092–6097

    Article  CAS  PubMed  Google Scholar 

  • Vellieux FM, Hajdu J, Verlinde CL, Groendijk H, Read RJ, Greenhough TJ, Campbell JW, Kalk KH, Littlechild JA, Watson HC et al (1993) Structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma brucei determined from Laue data. Proc Natl Acad Sci USA 90:2355–2359

    Article  CAS  PubMed  Google Scholar 

  • Verlinde CL, Hol WG (1994) Structure-based drug design: progress, results and challenges. Structure 2:577–587

    Article  CAS  PubMed  Google Scholar 

  • Vickers TJ, Greig N, Fairlamb AH (2004) A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major. Proc Natl Acad Sci USA 101:13186–13191

    Article  CAS  PubMed  Google Scholar 

  • Vivas J, Urbina JA, de SW (1996) Ultrastructural alterations in Trypanosoma (Schizotrypanum) cruzi induced by Delta(24(25)) sterol methyl transferase inhibitors and their combinations with ketoconazole. Int J Antimicrob Agents 7:235–240

    Article  CAS  PubMed  Google Scholar 

  • Werbovetz KA (2000) Target-based drug discovery for malaria, leishmaniasis, and trypanosomiasis. Curr Med Chem 7:835–860

    CAS  PubMed  Google Scholar 

  • Wierenga RK, Noble ME, Vriend G, Nauche S, Hol WG (1991) Refined 1.83 Å structure of trypanosomal triosephosphate isomerase crystallized in the presence of 2.4 M-ammonium sulphate. A comparison with the structure of the trypanosomal triosephosphate isomerase-glycerol-3-phosphate complex. J Mol Biol 220:995–1015

    Article  CAS  PubMed  Google Scholar 

  • Wiese M (1998) A mitogen-activated protein (MAP) kinase homologue of Leishmania mexicana is essential for parasite survival in the infected host. EMBO J 17:2619–2628

    Article  CAS  PubMed  Google Scholar 

  • Wiese M, Kuhn D, Grunfelder CG (2003) Protein kinase involved in flagellar-length control. Eukaryot Cell 2:769–777

    Article  CAS  PubMed  Google Scholar 

  • Williams JC, Zeelen JP, Neubauer G, Vriend G, Backmann J, Michels PA, Lambeir AM, Wierenga RK (1999) Structural and mutagenesis studies of leishmania triosephosphate isomerase: a point mutation can convert a mesophilic enzyme into a superstable enzyme without losing catalytic power. Protein Eng 12:243–250

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Bond CS, Bailey S, Cunningham ML, Fairlamb AH, Hunter WN (1996) The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 Å resolution. Protein Sci 5:52–61

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Rentala Madhubala is supported by a grant from Council of Scientific and Industrial Research (CSIR), India for the ongoing project related to hypusine biosynthesis. Bhavna Chawla is also supported by CSIR, India.

Author information

Authors and Affiliations

  1. School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Bhavna Chawla & Rentala Madhubala

Authors
  1. Bhavna Chawla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rentala Madhubala
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rentala Madhubala.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chawla, B., Madhubala, R. Drug targets in Leishmania . J Parasit Dis 34, 1–13 (2010). https://doi.org/10.1007/s12639-010-0006-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12639-010-0006-3

Keywords

Search

Navigation