Drug targets in Leishmania

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.

[1]  L. Hardy,et al.  Biochemical and Genetic Tests for Inhibitors ofLeishmaniaPteridine Pathways , 1997 .

[2]  W. de Souza,et al.  Growth inhibition and ultrastructural alterations induced by Δ24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms , 2009, BMC Microbiology.

[3]  A. Abbruzzese,et al.  Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. , 1986, The Journal of biological chemistry.

[4]  G Vriend,et al.  Refined 1.83 A 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. , 1991, Journal of molecular biology.

[5]  J. Berman,et al.  Allopurinol in the treatment of American cutaneous leishmaniasis. , 1992, The New England journal of medicine.

[6]  P. Myler,et al.  Searching the Tritryp Genomes for Drug Targets , 2008, Advances in experimental medicine and biology.

[7]  A. Crossman,et al.  Substrate specificity of the N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase of glycosylphosphatidylinositol membrane anchor biosynthesis in African trypanosomes and human cells. , 1997, The Biochemical journal.

[8]  A. Fairlamb,et al.  A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Caffrey,et al.  The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo , 2007, Kinetoplastid biology and disease.

[10]  P. Wilairat,et al.  In vitro study of anticancer acridines as potential antitrypanosomal and antimalarial agents , 1992, Antimicrobial Agents and Chemotherapy.

[11]  W. de Souza,et al.  In Vitro Activities of ER-119884 and E5700, Two Potent Squalene Synthase Inhibitors, against Leishmania amazonensis: Antiproliferative, Biochemical, and Ultrastructural Effects , 2008, Antimicrobial Agents and Chemotherapy.

[12]  M. Ferguson,et al.  The effects of phenylmethylsulfonyl fluoride on inositol-acylation and fatty acid remodeling in African trypanosomes. , 1994, The Journal of biological chemistry.

[13]  Michael D. Urbaniak,et al.  Probing enzymes late in the trypanosomal glycosylphosphatidylinositol biosynthetic pathway with synthetic glycosylphosphatidylinositol analogues. , 2008, ACS chemical biology.

[14]  M. Wiese.  A mitogen‐activated protein (MAP) kinase homologue of Leishmania mexicana is essential for parasite survival in the infected host , 1998, The EMBO journal.

[15]  J. Mottram,et al.  The CRK3 protein kinase is essential for cell cycle progression of Leishmania mexicana. , 2001, Molecular and biochemical parasitology.

[16]  L. Hardy,et al.  New approaches to Leishmania chemotherapy: pteridine reductase 1 (PTR1) as a target and modulator of antifolate sensitivity , 1997, Parasitology.

[17]  S. Phillips,et al.  The structure of pyruvate kinase from Leishmania mexicana reveals details of the allosteric transition and unusual effector specificity. , 1999, Journal of molecular biology.

[18]  L. Brinen,et al.  Crystal Structures of TbCatB and Rhodesain, Potential Chemotherapeutic Targets and Major Cysteine Proteases of Trypanosoma brucei , 2010, PLoS neglected tropical diseases.

[19]  J. Concepción,et al.  In Vitro and In Vivo Activities of E5700 and ER-119884, Two Novel Orally Active Squalene Synthase Inhibitors, against Trypanosoma cruzi , 2004, Antimicrobial Agents and Chemotherapy.

[20]  Characterization of the gene encoding glyoxalase II from Leishmania donovani: a potential target for anti-parasite drugs. , 2006, The Biochemical journal.

[21]  Heather J Munden,et al.  The Genome of the Kinetoplastid Parasite, Leishmania major , 2005, Science.

[22]  M. Attias,et al.  Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ24(25)-Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis , 2002, Antimicrobial Agents and Chemotherapy.

[23]  E. Oldfield,et al.  Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy. , 2001, Journal of medicinal chemistry.

[24]  N. Sen,et al.  Reconstitution and functional characterization of the unusual bi‐subunit type I DNA topoisomerase from Leishmania donovani , 2004, FEBS letters.

[25]  J. McKerrow,et al.  A Cathepsin B-like Protease Is Required for Host Protein Degradation in Trypanosoma brucei* , 2004, Journal of Biological Chemistry.

[26]  Conor R. Caffrey,et al.  A Parasite Cysteine Protease Is Key to Host Protein Degradation and Iron Acquisition*S⃞ , 2008, Journal of Biological Chemistry.

[27]  S. Beverley,et al.  Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  W. Hol,et al.  Structures of type 2 peroxisomal targeting signals in two trypanosomatid aldolases. , 2000, Journal of molecular biology.

[29]  A. Goswami,et al.  Dihydrobetulinic Acid Induces Apoptosis in Leishmania donovani by Targeting DNA Topoisomerase I and II: Implications in Antileishmanial Therapy , 2003, Molecular medicine.

[30]  L. Meijer,et al.  Inhibitors of Leishmania mexicana CRK3 Cyclin-Dependent Kinase: Chemical Library Screen and Antileishmanial Activity , 2004, Antimicrobial Agents and Chemotherapy.

[31]  I. Gilbert,et al.  Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis , 2004, Antimicrobial Agents and Chemotherapy.

[32]  Martin Olivier,et al.  Disruption of the trypanothione reductase gene of Leishmania decreases its ability to survive oxidative stress in macrophages , 1997, The EMBO journal.

[33]  A. Dasgupta,et al.  Topoisomerases of kinetoplastid parasites as potential chemotherapeutic targets. , 2004, Trends in parasitology.

[34]  G. H. Coombs,et al.  Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response. , 1998, Journal of immunology.

[35]  G Vriend,et al.  Structural and mutagenesis studies of leishmania triosephosphate isomerase: a point mutation can convert a mesophilic enzyme into a superstable enzyme without losing catalytic power. , 1999, Protein engineering.

[36]  K. Werbovetz,et al.  Antiprotozoal compounds from Psorothamnus polydenius. , 2005, Journal of natural products.

[37]  J. R. Brown,et al.  The GPI biosynthetic pathway as a therapeutic target for African sleeping sickness. , 1999, Biochimica et biophysica acta.

[38]  A. Fairlamb,et al.  The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 Å resolution , 1996, Protein science : a publication of the Protein Society.

[39]  Bradley E. Bernstein,et al.  Synergistic effects of substrate-induced conformational changes in phosphoglycerate kinase activation , 1997, Nature.

[40]  J. Wang,et al.  The TOP2 gene of Trypanosoma brucei: a single-copy gene that shares extensive homology with other TOP2 genes encoding eukaryotic DNA topoisomerase II. , 1990, Molecular and biochemical parasitology.

[41]  J. Marr,et al.  Allopurinol in the treatment of American cutaneous leishmaniasis. , 1992, The New England journal of medicine.

[42]  R. Docampo,et al.  The acidocalcisome as a target for chemotherapeutic agents in protozoan parasites. , 2008, Current pharmaceutical design.

[43]  R. Madhubala,et al.  Glyoxalase I Gene Deletion Mutants of Leishmania donovani Exhibit Reduced Methylglyoxal Detoxification , 2009, PloS one.

[44]  S. Landfear,et al.  An Acid-activated Nucleobase Transporter from Leishmania major* , 2009, The Journal of Biological Chemistry.

[45]  Daniel Kuhn,et al.  Protein Kinase Involved in Flagellar-Length Control , 2003, Eukaryotic Cell.

[46]  M. Ferguson,et al.  Glycosylphosphatidylinositol biosynthesis validated as a drug target for African sleeping sickness. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Terry K. Smith,et al.  Selective inhibitors of the glycosylphosphatidylinositol biosynthetic pathway of Trypanosoma brucei , 1999, The EMBO journal.

[48]  Terry K. Smith,et al.  Parasite and mammalian GPI biosynthetic pathways can be distinguished using synthetic substrate analogues , 1997, The EMBO journal.

[49]  M. H. Park,et al.  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). , 1982, The Journal of biological chemistry.

[50]  K. Kashiwagi,et al.  Independent roles of eIF5A and polyamines in cell proliferation. , 2005, The Biochemical journal.

[51]  W. Hockmeyer,et al.  Allopurinol in the treatment of visceral leishmaniasis. , 1981, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[52]  A. Bodley,et al.  Antitrypanosomal activity of camptothecin analogs. Structure-activity correlations. , 1995, Biochemical pharmacology.

[53]  W. Souza,et al.  Alterations Induced by the Antifungal Compounds Ketoconazole and Terbinafine in Leishmania , 1995, The Journal of eukaryotic microbiology.

[54]  F. Opperdoes.  Compartmentation of carbohydrate metabolism in trypanosomes. , 1987, Annual review of microbiology.

[55]  Daniel Kuhn,et al.  LmxMPK9, a mitogen‐activated protein kinase homologue affects flagellar length in Leishmania mexicana , 2005, Molecular microbiology.

[56]  T. Shiba,et al.  Hypusine, a new amino acid occurring in bovine brain. Isolation and structural determination. , 1971, Biochimica et biophysica acta.

[57]  S. Goldenberg,et al.  Cloning and characterization of the gene encoding Trypanosoma cruzi DNA topoisomerase II. , 1992, Molecular and biochemical parasitology.

[58]  R. Madhubala,et al.  Identification and Characterization of a Novel Deoxyhypusine Synthase in Leishmania donovani* , 2009, The Journal of Biological Chemistry.

[59]  Q. Dou,et al.  NAD+ stimulated the spermidine‐dependent hypusine formation on the 18 kDa protein in cytosolic lysates derived from NB‐15 mouse neuroblastoma cells , 1988, FEBS letters.

[60]  J. Champoux,et al.  The structure of the transition state of the heterodimeric topoisomerase I of Leishmania donovani as a vanadate complex with nicked DNA. , 2006, Journal of molecular biology.

[61]  Terry K. Smith,et al.  Specificity of GlcNAc‐PI de‐N‐acetylase of GPI biosynthesis and synthesis of parasite‐specific suicide substrate inhibitors , 2001, The EMBO journal.

[62]  P. Myler,et al.  Glyoxalase I from Leishmania donovani: a potential target for anti-parasite drug. , 2005, Biochemical and biophysical research communications.

[63]  Beverley,et al.  Biochemical and Genetic Tests for Inhibitors of Leishmania Pteridine Pathways , 1997, Experimental parasitology.

[64]  '. FREDM.D.VELLIEUXa,et al.  Structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma brucei determined from Laue data. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[65]  S. Croft,et al.  An in-vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani. , 1984, The Journal of antimicrobial chemotherapy.

[66]  A. Remaley,et al.  Biochemistry of the Leishmania species. , 1988, Microbiological reviews.

[67]  J. Mottram,et al.  The crk3 Gene of Leishmania mexicanaEncodes a Stage-regulated cdc2-related Histone H1 Kinase That Associates with p12 cks1 * , 1998, The Journal of Biological Chemistry.

[68]  S. Landfear,et al.  Point mutations in a nucleoside transporter gene from Leishmania donovani confer drug resistance and alter substrate selectivity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[69]  W. de Souza,et al.  Ultrastructural alterations in Trypanosoma (Schizotrypanum) cruzi induced by Delta(24(25)) sterol methyl transferase inhibitors and their combinations with ketoconazole. , 1996, International journal of antimicrobial agents.

[70]  S. Landfear,et al.  Cloning of a Novel Inosine-Guanosine Transporter Gene fromLeishmania donovani by Functional Rescue of a Transport-deficient Mutant* , 2000, The Journal of Biological Chemistry.

[71]  C L Verlinde,et al.  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. , 1995, Biochemistry.

[72]  R. Krauth-Siegel,et al.  Glyoxalase II of African Trypanosomes Is Trypanothione-dependent* , 2004, Journal of Biological Chemistry.

[73]  A. Abbruzzese,et al.  Deoxyhypusine hydroxylase. , 2020, Advances in Experimental Medicine and Biology.

[74]  R. Pink,et al.  Opportunities and Challenges in Antiparasitic Drug Discovery , 2005, Nature Reviews Drug Discovery.

[75]  K. Werbovetz.  Target-based drug discovery for malaria, leishmaniasis, and trypanosomiasis. , 2000, Current medicinal chemistry.

[76]  A. Dasgupta,et al.  Characterisation of the gene encoding type II DNA topoisomerase from Leishmania donovani: a key molecular target in antileishmanial therapy. , 2001, Nucleic acids research.

[77]  B. Chait,et al.  Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids. , 1985, Science.

[78]  The N-Acetyl-D-glucosaminylphosphatidylinositol De-N-acetylase of Glycosylphosphatidylinositol Biosynthesis Is a , 2005 .

[79]  I. Kuntz,et al.  Rational design of novel antimicrobials: blocking purine salvage in a parasitic protozoan. , 1998, Biochemistry.

[80]  R A Cooper,et al.  Metabolism of methylglyoxal in microorganisms. , 1984, Annual review of microbiology.

[81]  F. Opperdoes,et al.  Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[82]  G. H. Coombs,et al.  Overexpression of the Natural Inhibitor of Cysteine Peptidases in Leishmania mexicana Leads to Reduced Virulence and a Th1 Response , 2009, Infection and Immunity.

[83]  M. H. Park,et al.  Antiproliferative effects of inhibitors of deoxyhypusine synthase. Inhibition of growth of Chinese hamster ovary cells by guanyl diamines. , 1994, The Journal of biological chemistry.

[84]  J. Marr.  Pyrazolopyrimidine metabolism in Leishmania and Trypanosomes: Significant differences between host and parasite , 1983, Journal of cellular biochemistry.

[85]  W G Hol,et al.  A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana. , 2000, Structure.

[86]  Terry K. Smith,et al.  The N-Acetyl-D-glucosaminylphosphatidylinositol De-N-acetylase of Glycosylphosphatidylinositol Biosynthesis Is a Zinc Metalloenzyme* , 2005, Journal of Biological Chemistry.

[87]  C L Verlinde,et al.  Structure-based drug design: progress, results and challenges. , 1994, Structure.

[88]  I. Gilbert,et al.  Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi. , 2003, Journal of medicinal chemistry.

[89]  M. Barrett,et al.  Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. , 1999, Trends in microbiology.

[90]  J. Hershey,et al.  Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae , 1991, Molecular and cellular biology.

[91]  S. Beverley,et al.  The role of phosphoglycans in Leishmania-sand fly interactions. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[92]  K. Kang,et al.  Deoxyhypusine Synthase Activity Is Essential for Cell Viability in the Yeast Saccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.

[93]  E. Gerner,et al.  Hypusine formation in protein by a two-step process in cell lysates. , 1987, The Journal of biological chemistry.

[94]  N. Carter,et al.  Point mutations within the LdNT2 nucleoside transporter gene from Leishmania donovani confer drug resistance and transport deficiency. , 2006, The international journal of biochemistry & cell biology.

[95]  S. Beverley,et al.  Cloning of Leishmania nucleoside transporter genes by rescue of a transport-deficient mutant. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[96]  R. B. Loftfield.  The biosynthesis of protein. , 1957, Progress in biophysics and biophysical chemistry.

[97]  D. Nelson,et al.  Inosine analogs as chemotherapeutic agents for African trypanosomes: metabolism in trypanosomes and efficacy in tissue culture , 1985, Antimicrobial Agents and Chemotherapy.