Protein farnesyl and N-myristoyl transferases: piggy-back medicinal chemistry targets for the development of antitrypanosomatid and antimalarial therapeutics.

To accelerate progress in the development of therapeutics for protozoan parasitic diseases, we are studying enzymes active in co- and post-translational protein modification that are already the focus of drug development in other eukaryotic systems. Inhibitors of the protein farnesyltransferases (PFT) are well-established antitumour agents of low cytotoxicity and known pharmokinetic properties, while inhibitors of N-myristoyl transferase show both selectivity and specificity in the treatment of fungal infections. Here, we summarise the current evidence that supports the targeting of these ubiquitous eukaryotic enzymes for drug development against trypanosomatid infections and malaria.

[1]  B Honig,et al.  Electrostatic interaction of myristoylated proteins with membranes: simple physics, complicated biology. , 1997, Structure.

[2]  M. Gelb,et al.  Cloning, Heterologous Expression, and Distinct Substrate Specificity of Protein Farnesyltransferase from Trypanosoma brucei * , 2000, The Journal of Biological Chemistry.

[3]  B. Cravatt,et al.  A Second Mammalian N-Myristoyltransferase* , 1998, The Journal of Biological Chemistry.

[4]  P. T. Englund,et al.  Fatty acid synthesis in African trypanosomes: a solution to the myristate mystery. , 2001, Trends in parasitology.

[5]  M. Gelb,et al.  Prenyl proteins in eukaryotic cells: a new type of membrane anchor. , 1990, Trends in biochemical sciences.

[6]  M. Gelb,et al.  Binding of the delta subunit to rod phosphodiesterase catalytic subunits requires methylated, prenylated C-termini of the catalytic subunits. , 2000, Biochemistry.

[7]  Zhanghua Wu,et al.  Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue. , 1998, Biochemistry.

[8]  J. Gordon,et al.  Genetic and biochemical studies of protein N-myristoylation. , 1994, Annual review of biochemistry.

[9]  J. Gordon,et al.  Disruption of the yeast N-myristoyl transferase gene causes recessive lethality. , 1989, Science.

[10]  T. Furuya,et al.  A Novel Phosphatidylinositol-Phospholipase C of Trypanosoma cruzi That Is Lipid Modified and Activated during Trypomastigote to Amastigote Differentiation* , 2000, The Journal of Biological Chemistry.

[11]  Andrej ⩽ali,et al.  Comparative protein modeling by satisfaction of spatial restraints , 1995 .

[12]  A. Aderem,et al.  The myristoyl-electrostatic switch: a modulator of reversible protein-membrane interactions. , 1995, Trends in biochemical sciences.

[13]  M. Resh Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. , 1999, Biochimica et biophysica acta.

[14]  J. Gordon,et al.  The structure of myristoyl-CoA:protein N-myristoyltransferase. , 1999, Biochimica et biophysica acta.

[15]  G. Hart,et al.  An analog of myristic acid with selective toxicity for African trypanosomes. , 1991, Science.

[16]  P. McKean,et al.  Characterisation of a second protein encoded by the differentially regulated LmcDNA16 gene family of Leishmania major. , 1997, Molecular and biochemical parasitology.

[17]  Mark C. Field,et al.  Characterisation of protein isoprenylation in procyclic form Trypanosoma brucei. , 1996, Molecular and biochemical parasitology.

[18]  N. Kohl,et al.  Farnesyltransferase inhibitors: a new class of cancer chemotherapeutics. , 1996, Biochemical Society transactions.

[19]  R. Geahlen,et al.  Metabolic activation of 2-substituted derivatives of myristic acid to form potent inhibitors of myristoyl CoA:protein N-myristoyltransferase. , 1990, Biochemistry.

[20]  D. Engman,et al.  Flagellar protein localization mediated by a calcium–myristoyl/palmitoyl switch mechanism , 1999, The EMBO journal.

[21]  D. C. Wood,et al.  Genetic studies reveal that myristoylCoA:protein N‐myristoyltransferase is an essential enzyme in Candida albicans , 1995, Molecular microbiology.

[22]  Mark C. Field,et al.  Acylation-dependent Protein Export inLeishmania * , 2000, The Journal of Biological Chemistry.

[23]  A. Kral,et al.  Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice , 1995, Nature Medicine.

[24]  J. Irwin,et al.  Crystal structure of the anti-fungal target N-myristoyl transferase , 1998, Nature Structural Biology.

[25]  M. Gelb,et al.  TcRho1, a Farnesylated Rho Family Homologue from Trypanosoma cruzi , 2001, The Journal of Biological Chemistry.

[26]  K. Gull,et al.  CAP5.5, a life-cycle-regulated, cytoskeleton-associated protein is a member of a novel family of calpain-related proteins in Trypanosoma brucei. , 2001, Molecular and biochemical parasitology.

[27]  S. Sebti,et al.  Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines , 1997, Oncogene.

[28]  J. Gordon,et al.  Kinetic and structural evidence for a sequential ordered Bi Bi mechanism of catalysis by Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase. , 1991, The Journal of biological chemistry.

[29]  K. Stuart,et al.  The effects of protein farnesyltransferase inhibitors on trypanosomatids: inhibition of protein farnesylation and cell growth. , 1998, Molecular and biochemical parasitology.

[30]  P. Kaye,et al.  Immunization with a Recombinant Stage-Regulated Surface Protein from Leishmania donovani Induces Protection Against Visceral Leishmaniasis1 , 2000, The Journal of Immunology.

[31]  J. Karp,et al.  Current status of clinical trials of farnesyltransferase inhibitors , 2001, Current opinion in oncology.

[32]  J. Lodge,et al.  Design and synthesis of novel imidazole-substituted dipeptide amides as potent and selective inhibitors of Candida albicans myristoylCoA:protein N-myristoyltransferase and identification of related tripeptide inhibitors with mechanism-based antifungal activity. , 1997, Journal of medicinal chemistry.

[33]  K. Stuart,et al.  Prenylation of proteins in Trypanosoma brucei. , 1997, Molecular and biochemical parasitology.

[34]  J. Lodge,et al.  Genetic and Biochemical Studies Establish That the Fungicidal Effect of a Fully Depeptidized Inhibitor of Cryptococcus neoformans Myristoyl-CoA:ProteinN-Myristoyltransferase (Nmt) Is Nmt-dependent* , 1998, The Journal of Biological Chemistry.

[35]  N. Gay,et al.  Drosophila embryos lacking N-myristoyltransferase have multiple developmental defects. , 2001, Experimental cell research.

[36]  T. Sasaki,et al.  Purification and characterization from bovine brain cytosol of a protein that inhibits the dissociation of GDP from and the subsequent binding of GTP to smg p25A, a ras p21-like GTP-binding protein. , 1990, The Journal of biological chemistry.

[37]  S. Cordo,et al.  Myristic acid analogs are inhibitors of Junin virus replication. , 1999, Microbes and infection.

[38]  J. Lodge,et al.  Comparison of myristoyl-CoA:protein N-myristoyltransferases from three pathogenic fungi: Cryptococcus neoformans, Histoplasma capsulatum, and Candida albicans. , 1994, The Journal of biological chemistry.

[39]  P. Casey,et al.  Biochemistry of protein prenylation. , 1992, Journal of lipid research.

[40]  D. Chakrabarti,et al.  Protein prenyl transferase activities of Plasmodium falciparum. , 1998, Molecular and biochemical parasitology.

[41]  Anthony A. Holder,et al.  Characterization of N-myristoyltransferase from Plasmodium falciparum. , 2000 .

[42]  S. Croft,et al.  Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity. , 2001, Bioorganic & medicinal chemistry letters.

[43]  J. Lodge,et al.  N-myristoylation of Arf proteins in Candida albicans: an in vivo assay for evaluating antifungal inhibitors of myristoyl-CoA: protein N-myristoyltransferase. , 1997, Microbiology.

[44]  K. D. Hartman,et al.  Human N-Myristoyltransferase Amino-terminal Domain Involved in Targeting the Enzyme to the Ribosomal Subcellular Fraction* , 1997, The Journal of Biological Chemistry.

[45]  Protein prenyltransferases : Isoprenoids - Biosynthesis and role in the regulation of protein function , 1992 .

[46]  G Waksman,et al.  The biology and enzymology of protein N-myristoylation. , 2001, The Journal of biological chemistry.

[47]  D. Goulding,et al.  Myristoyl-CoA:Protein N-Myristoyltransferase, an Essential Enzyme and Potential Drug Target in Kinetoplastid Parasites* , 2003, The Journal of Biological Chemistry.

[48]  M. Gelb,et al.  Geranylgeranylated proteins : Molecular and immunological approaches to the study of synaptic and axonal glycoproteins , 1992 .

[49]  R. Datla,et al.  Molecular Cloning, Genomic Organization, and Biochemical Characterization of Myristoyl-CoA:ProteinN-Myristoyltransferase from Arabidopsis thaliana * , 2000, The Journal of Biological Chemistry.

[50]  M. Gelb,et al.  Geranylgeranylated proteins. , 1992, Biochemical Society Transactions.

[51]  C. Marshall,et al.  A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21 ras to the plasma membrane , 1990, Cell.

[52]  M. Gelb,et al.  Brain G protein gamma subunits contain an all-trans-geranylgeranylcysteine methyl ester at their carboxyl termini. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Helen M. Flinn,et al.  Expression of a hydrophilic surface protein in infective stages of Leishmania major. , 1994, Molecular and biochemical parasitology.

[54]  Mark C. Field,et al.  GTPases in protozoan parasites: tools for cell biology and chemotherapy. , 1999, Parasitology today.

[55]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[56]  G. Hart,et al.  Toxicity of myristic acid analogs toward African trypanosomes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Gelb,et al.  The δ Subunit of Type 6 Phosphodiesterase Reduces Light-induced cGMP Hydrolysis in Rod Outer Segments* , 2001, The Journal of Biological Chemistry.