Prenyldiphosphate Synthase Inhibitors: Novel Anti-Infective Agents

Summary

Principal Investigator: Eric Oldfield
Affiliation: University of Illinois
Country: USA
Abstract: The broad, overall objective of this work is to develop novel anti-infective agents which target the isoprene biosynthesis pathways in protozoa and bacteria by using a combination of x-ray crystallography, NMR spectroscopy, calorimetry, enzyme and cell growth inhibition assays, QSAR (quantitative structure-activity relationship) techniques, quantum chemistry, synthesis, drug delivery and animal testing. The First Specific Aim is to use x-ray crystallography and solid-state NMR spectroscopy to investigate the structures of novel inhibitors bound to, primarily, farnesyl diphosphate synthase (FPPS) from Trypanosoma cruzi (the causative agent of American trypanosomiasis or Chagas disease), Trypanosoma brucei (the causative agent of African sleeping sickness), E. coli and Staphylococcus aureus, as well as human FPPS (the target for the bisphosphonate drugs used in treating bone resorption diseases, of interest in the context of designing inhibitor selectivity). Solid-state NMR will be used to complement the crystallographic results by providing dynamics (from 2H NMR) and protonation state information (from 13C, 15N, 31P chemical shifts) for use in the QSAR investigations. The Second Specific Aim is to investigate structure-function relationships. We will investigate inhibitor binding by using isothermal titration calorimetry and differential scanning calorimetry, as well as by using classical enzyme inhibition techniques, to deduce ligand binding constants (KB) and Kis together with thermodynamics of binding information for the systems studied in Aim 1. In addition, inhibitor binding to human bone and bone mineral models will be investigated using chromatographic and NMR techniques. These results will all then be analyzed by using QSAR methods, including the use of differential QSAR methods (to optimize parasite/bacterial inhibition versus human FPPS inhibition, and to minimize bone adsorption), together with the use of non-conventional QM descriptors and 2H NMR order parameters, to enhance the predictive utility of these methods. The Third and Final Specific Aim is to use the results from Aims 1 and 2 to design and then synthesize specific inhibitors of the isoprene biosynthesis pathway. These inhibitors will include novel pyridium, sulfonium and phosphonium species and will be designed to target unique polar residues found in the active site of the protozoal and bacterial enzymes. These inhibitors will then be formulated in bioavailable forms for use in animal testing. We will also focus on synergistic or combination therapy approaches by using two or three compounds, each of which target the isoprene biosynthesis pathway: such strongly synergistic interactions have already been observed and now need to be optimized using the novel inhibitors. Lay Summary: The research proposed is designed to lead to new therapeutic approaches to treat a variety of infectious diseases. In the US, these diseases are primarily bacterial and are a major public health threat while in the rest of the world, infectious diseases are mainly caused by protozoa. This work seeks to develop drugs to treat both sorts of disease.
Funding Period: 2002-06-01 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Iron porphyrin carbenes as catalytic intermediates: structures, mössbauer and NMR spectroscopic properties, and bonding
    Rahul L Khade
    Department of Chemistry, Chemical Biology, and Biomedical, Engineering, Stevens Institute of Technology, Castle Point on Hudson, Hoboken, NJ 07030 USA
    Angew Chem Int Ed Engl 53:7574-8. 2014
  2. pmc Structure, function and inhibition of the two- and three-domain 4Fe-4S IspG proteins
    Yi Liang Liu
    Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 109:8558-63. 2012
  3. pmc Are free radicals involved in IspH catalysis? An EPR and crystallographic investigation
    Weixue Wang
    Center for Biophysics and Computational Biology, 607 South Mathews Avenue, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Am Chem Soc 134:11225-34. 2012
  4. pmc Discovery of acetylene hydratase activity of the iron-sulphur protein IspH
    Ingrid Span
    Department of Chemistry, Center for Integrated Protein Science, Technische Universitat Munchen, Lichtenbergstrasse 4, 85747 Garching, Germany
    Nat Commun 3:1042. 2012
  5. pmc Antibacterial drug leads targeting isoprenoid biosynthesis
    Wei Zhu
    Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 110:123-8. 2013
  6. pmc Structures of Fluoro, Amino, and Thiol Inhibitors Bound to the [Fe(4) S(4) ] Protein IspH
    Ingrid Span
    Center for Integrated Protein Science Munich, Chemie Department, Technische Universitat Munchen, Lichtenbergstrasse 4, 85747 Garching Germany http www biochemie ch tum de
    Angew Chem Int Ed Engl 52:2118-21. 2013
  7. pmc Insights into TIM-barrel prenyl transferase mechanisms: crystal structures of PcrB from Bacillus subtilis and Staphylococcus aureus
    Feifei Ren
    Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 XiQiDao, Tianjin 300308, China
    Chembiochem 14:195-9. 2013
  8. pmc Isoprenoid Biosynthesis: Ferraoxetane or Allyl Anion Mechanism for IspH Catalysis?
    Jikun Li
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 607 South Mathews Avenue, Urbana, IL 61801 USA
    Angew Chem Int Ed Engl 52:6522-5. 2013
  9. pmc Characterization of potential drug targets farnesyl diphosphate synthase and geranylgeranyl diphosphate synthase in Schistosoma mansoni
    Peter D Ziniel
    School of Biological Sciences, Illinois State University, Normal, Illinois, USA
    Antimicrob Agents Chemother 57:5969-76. 2013
  10. pmc Squalene synthase as a target for chagas disease therapeutics
    Na Shang
    Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
    PLoS Pathog 10:e1004114. 2014

Scientific Experts

  • Roberto Docampo
  • Jacob D Durrant
  • Agam Prasad Singh
  • William Sinko
  • Eric Oldfield
  • Weixue Wang
  • Ke Wang
  • Yongcheng Song
  • Yonghui Zhang
  • Rong Cao
  • Yi Liang Liu
  • Jikun Li
  • Rey Ting Guo
  • Joo Hwan No
  • Andrew H J Wang
  • Yong Zhang
  • Michael P Hudock
  • Ingrid Span
  • Wei Zhu
  • Dushyant Mukkamala
  • Sujoy Mukherjee
  • Tzu Ping Ko
  • Fenglin Yin
  • Fu Yang Lin
  • Hsiu Chien Chan
  • Yan Ling
  • Cancan Huang
  • Gustavo Benaim
  • Julian M W Chan
  • Victor Nizet
  • Sandra B Gabelli
  • Julio A Urbina
  • Chun Hsiang Huang
  • Rahul L Khade
  • Feifei Ren
  • Xinxin Feng
  • Kai Li
  • Michael Groll
  • Adelbert Bacher
  • Tatyana I Smirnova
  • Dolores Gonzalez-Pacanowska
  • John M Sanders
  • L Mario Amzel
  • Po Huang Liang
  • Ting Kai Chang
  • Chia I Liu
  • Wen Yih Jeng
  • Kildare Miranda
  • Na Shang
  • Srinivas Aripirala
  • Yingying Zheng
  • Chun Chi Chen
  • Esteban L Ravaschino
  • Yumei Hu
  • Peter D Ziniel
  • Sarah Odeh
  • Evangelia Kotsikorou
  • Johann Jauch
  • Wolfgang Eisenreich
  • Wanderley de Souza
  • Zhu Hong Li
  • Mary E Hensler
  • Francisco Guerra
  • Juan Luis Concepcion
  • Jean Daniel Compain
  • Isabela B Ramos
  • Chuan Hsiang Huang
  • Mary Hensler
  • Kilannin Krysiak
  • George Y Liu
  • Kyle Bergan
  • Cammy K-M Chen
  • Cammy K M Chen
  • Amanda Goddard
  • Yi Gui Gao
  • Tao Hsin Chang
  • Craig T Morita
  • Hong Wang
  • Carlos E Sanz-Rodríguez
  • Zev Tovian
  • Marcela Ferella
  • Annette Leon-Rossell
  • Andrea Montalvetti
  • Silvia N J Moreno
  • Junhong Mao
  • Juan B Rodriguez
  • Gary A Meints
  • Thomas Kosztowski
  • Sergio H Szajnman
  • Wenting Liu

Detail Information

Publications56

  1. pmc Iron porphyrin carbenes as catalytic intermediates: structures, mössbauer and NMR spectroscopic properties, and bonding
    Rahul L Khade
    Department of Chemistry, Chemical Biology, and Biomedical, Engineering, Stevens Institute of Technology, Castle Point on Hudson, Hoboken, NJ 07030 USA
    Angew Chem Int Ed Engl 53:7574-8. 2014
    ..The preferred resonance structure is Fe(II) ←{:C(X)Y}(0) and not Fe(IV) {C(X)Y}(2-) , a result that will facilitate research on IPC reactivities in various chemical and biochemical systems. ..
  2. pmc Structure, function and inhibition of the two- and three-domain 4Fe-4S IspG proteins
    Yi Liang Liu
    Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 109:8558-63. 2012
    ....
  3. pmc Are free radicals involved in IspH catalysis? An EPR and crystallographic investigation
    Weixue Wang
    Center for Biophysics and Computational Biology, 607 South Mathews Avenue, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Am Chem Soc 134:11225-34. 2012
    ..Additionally, we show by using EPR spectroscopy and X-ray crystallography that two substrate analogues (4 and 5) follow the same reaction mechanism...
  4. pmc Discovery of acetylene hydratase activity of the iron-sulphur protein IspH
    Ingrid Span
    Department of Chemistry, Center for Integrated Protein Science, Technische Universitat Munchen, Lichtenbergstrasse 4, 85747 Garching, Germany
    Nat Commun 3:1042. 2012
    ..This unexpected side to IspH reactivity is of interest in the context of the mechanism of action of other acetylene hydratases, as well as in the design of antiinfectives targeting IspH...
  5. pmc Antibacterial drug leads targeting isoprenoid biosynthesis
    Wei Zhu
    Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 110:123-8. 2013
    ..25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies...
  6. pmc Structures of Fluoro, Amino, and Thiol Inhibitors Bound to the [Fe(4) S(4) ] Protein IspH
    Ingrid Span
    Center for Integrated Protein Science Munich, Chemie Department, Technische Universitat Munchen, Lichtenbergstrasse 4, 85747 Garching Germany http www biochemie ch tum de
    Angew Chem Int Ed Engl 52:2118-21. 2013
    ..Crystal structures of IspH complexed with three substrate analogues reveal their mode of binding and suggest new routes to inhibitor design...
  7. pmc Insights into TIM-barrel prenyl transferase mechanisms: crystal structures of PcrB from Bacillus subtilis and Staphylococcus aureus
    Feifei Ren
    Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 XiQiDao, Tianjin 300308, China
    Chembiochem 14:195-9. 2013
    ....
  8. pmc Isoprenoid Biosynthesis: Ferraoxetane or Allyl Anion Mechanism for IspH Catalysis?
    Jikun Li
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 607 South Mathews Avenue, Urbana, IL 61801 USA
    Angew Chem Int Ed Engl 52:6522-5. 2013
    ..The results indicate the formation of an allyl anion bound to a HiPIP-like oxidized 4Fe-4S cluster, rather than formation of a cyclic, ferraoxetane intermediate, as has been proposed elsewhere...
  9. pmc Characterization of potential drug targets farnesyl diphosphate synthase and geranylgeranyl diphosphate synthase in Schistosoma mansoni
    Peter D Ziniel
    School of Biological Sciences, Illinois State University, Normal, Illinois, USA
    Antimicrob Agents Chemother 57:5969-76. 2013
    ..These results indicate that FPPS and GGPPS could be of interest in the context of the emerging resistance to praziquantel in schistosomiasis therapy. ..
  10. pmc Squalene synthase as a target for chagas disease therapeutics
    Na Shang
    Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
    PLoS Pathog 10:e1004114. 2014
    ....
  11. pmc Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates
    Srinivas Aripirala
    Institute for Multiscale Modeling of Biological Interactions and Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, 725 North Wolfe Street WBSB 605, Baltimore, MD 21210, USA
    Acta Crystallogr D Biol Crystallogr 70:802-10. 2014
    ..It is proposed that IPP first binds to the open site, which then closes, opening the site on the other monomer, which closes after binding the second IPP, leading to the symmetric fully occupied FPPS dimer observed in other structures. ..
  12. pmc Dronedarone, an amiodarone analog with improved anti-Leishmania mexicana efficacy
    Gustavo Benaim
    Laboratorio de Señalización Celular y Bioquímica de Parásitos, Instituto de Estudios Avanzados IDEA, Caracas, Venezuela
    Antimicrob Agents Chemother 58:2295-303. 2014
    ..Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases...
  13. pmc Bioorganometallic chemistry with IspG and IspH: structure, function, and inhibition of the [Fe(4)S(4)] proteins involved in isoprenoid biosynthesis
    Weixue Wang
    Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
    Angew Chem Int Ed Engl 53:4294-310. 2014
    ..The results presented support bioorganometallic catalytic mechanisms for IspG and IspH, and open up new routes to anti-infective drug design targeting [Fe4 S4 ] clusters in proteins. ..
  14. pmc Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from Mycobacterium tuberculosis
    Hsiu Chien Chan
    Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Tianjin 300308, China
    J Am Chem Soc 136:2892-6. 2014
    ..tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here. ..
  15. pmc Calcium- and polyphosphate-containing acidic granules of sea urchin eggs are similar to acidocalcisomes, but are not the targets for NAADP
    Isabela B Ramos
    Department of Cellular Biology, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, 30602, USA
    Biochem J 429:485-95. 2010
    ....
  16. pmc Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG)
    Weixue Wang
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 607 South Mathews Avenue, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 107:11189-93. 2010
    ..Overall, the results are of broad general interest because they provide new mechanistic insights into GcpE catalysis and inhibition, with organometallic bond formation playing, in both cases, a key role...
  17. pmc Targeting isoprenoid biosynthesis for drug discovery: bench to bedside
    Eric Oldfield
    Department of Chemistry, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    Acc Chem Res 43:1216-26. 2010
    ....
  18. pmc Diterpene cyclases and the nature of the isoprene fold
    Rong Cao
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA
    Proteins 78:2417-32. 2010
    ..The results support a new view of terpene cyclase structure and function and suggest evolution from ancient (betagamma) bacterial triterpene cyclases to (betagamma) bacterial and thence to (alphabetagamma) plant diterpene cyclases...
  19. pmc Tetra- to dodecanuclear oxomolybdate complexes with functionalized bisphosphonate ligands: activity in killing tumor cells
    Jean Daniel Compain
    Institut Lavoisier de Versailles, UMR CNRS 8180, Universite de Versailles Saint Quentin, 78035 Versailles Cedex, France
    Chemistry 16:13741-8. 2010
    ....
  20. pmc Applying molecular dynamics simulations to identify rarely sampled ligand-bound conformational states of undecaprenyl pyrophosphate synthase, an antibacterial target
    William Sinko
    Department of Chemistry and Biochemistry, and NSF Center for Theoretical Biological Physics, University of California San Diego, La Jolla, USA
    Chem Biol Drug Des 77:412-20. 2011
    ..We believe that this is the first time that a rare 'expanded pocket' state, key to drug design and verified by crystallography, has been extracted from a molecular dynamics simulation...
  21. pmc An ENDOR and HYSCORE investigation of a reaction intermediate in IspG (GcpE) catalysis
    Weixue Wang
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Am Chem Soc 133:8400-3. 2011
    ..These results help clarify the nature of the reaction intermediate, supporting a direct interaction between the unique fourth Fe in the cluster and C2 and O3 of the ligand...
  22. pmc Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design
    Jacob D Durrant
    Department of Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, CA 92093, USA
    Chem Biol Drug Des 78:323-32. 2011
    ..These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads...
  23. pmc Terpene biosynthesis: modularity rules
    Eric Oldfield
    Department of Chemistry and Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA
    Angew Chem Int Ed Engl 51:1124-37. 2012
    ..We also review progress in determining the structure and function of the two 4Fe-4S reductases involved in formation of the C(5) diphosphates in many bacteria, where again, highly modular structures are found...
  24. pmc Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity
    Joo Hwan No
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 109:4058-63. 2012
    ....
  25. pmc Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth
    Agam Prasad Singh
    National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
    Antimicrob Agents Chemother 54:2987-93. 2010
    ..Lipophilic bisphosphonates are thus promising leads for novel antimalarials that target liver-stage infection...
  26. pmc Inhibition of the Fe(4)S(4)-cluster-containing protein IspH (LytB): electron paramagnetic resonance, metallacycles, and mechanisms
    Ke Wang
    Department of Chemistry, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Am Chem Soc 132:6719-27. 2010
    ....
  27. pmc Bioorganometallic mechanism of action, and inhibition, of IspH
    Weixue Wang
    Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 107:4522-7. 2010
    ..Overall, the results are of broad general interest because they provide new insights into IspH catalysis and inhibition, involving organometallic species, and may be applicable to other Fe(4)S(4)-containing proteins, such as IspG...
  28. pmc Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer
    Chuan Hsiang Huang
    Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Proteins 78:888-99. 2010
    ..This mechanism of binding of N-BPs to TcFPPS is different to that reported for the binding of the same compounds to human FPPS. Proteins 2010. (c) 2009 Wiley-Liss, Inc...
  29. pmc Pyridine inhibitor binding to the 4Fe-4S protein A. aeolicus IspH (LytB): a HYSCORE Investigation
    Weixue Wang
    Center for Biophysics and Computational Biology, 607 South Mathews Avenue, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Am Chem Soc 133:6525-8. 2011
    ....
  30. ncbi Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes
    Junhong Mao
    Department of Chemistry and Biophysics, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Am Chem Soc 128:14485-97. 2006
    ....
  31. ncbi A solanesyl-diphosphate synthase localizes in glycosomes of Trypanosoma cruzi
    Marcela Ferella
    Instituto Nacional de Parasitologia Dr M Fatala Chaben, Av Paseo Colon 568, Administracion Nacional de Laboratorios e Institutos de Salud, Ministerio de Salud, Buenos Aires 1063, Argentina
    J Biol Chem 281:39339-48. 2006
    ..Because UQ has a central role in energy production and in reoxidation of reduction equivalents, TcSPPS is promising as a new chemotherapeutic target...
  32. ncbi Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase
    Fenglin Yin
    Department of Biophysics, University of Illinois at Urbana Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Am Chem Soc 128:3524-5. 2006
    ....
  33. ncbi Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole
    Gustavo Benaim
    Laboratorio Química Biológica and Laboratorio de Permeabilidad Iónica, Instituto Venezolano de Investigaciones Cientificas, Apartado 21927, Caracas 1020A, Venezuela
    J Med Chem 49:892-9. 2006
    ..cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs...
  34. ncbi Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis
    Esteban L Ravaschino
    Departamento de Quimica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2, Ciudad Universitaria, C1428EHA, Buenos Aires, Argentina
    J Med Chem 49:426-35. 2006
    ..The simple phosphinopeptide structure found as a pharmacophore in the present study constitutes a starting point for the development of straightforward optimized drugs...
  35. ncbi Inhibition of Trypanosoma cruzi hexokinase by bisphosphonates
    Michael P Hudock
    Department of Biophysics, University of Illinois at Urbana Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Med Chem 49:215-23. 2006
    ..2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi...
  36. ncbi Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: implications for drug design
    Sandra B Gabelli
    Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
    Proteins 62:80-8. 2006
    ....
  37. ncbi Bisphosphonate inhibition of the exopolyphosphatase activity of the Trypanosoma brucei soluble vacuolar pyrophosphatase
    Evangelia Kotsikorou
    Department of Chemistry, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Med Chem 48:6128-39. 2005
    ..brucei infection. The most active compound in vivo provided a 40% protection from death with no apparent side effects, suggesting that further development of such compounds may be of interest...
  38. ncbi Synthesis and biological evaluation of 1-amino-1,1-bisphosphonates derived from fatty acids against Trypanosoma cruzi targeting farnesyl pyrophosphate synthase
    Sergio H Szajnman
    Departamento de Quimica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon 2, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
    Bioorg Med Chem Lett 15:4685-90. 2005
    ..cruzi farnesyl pyrophosphate synthase. As bisphosphonate-containing drugs are FDA-approved for the treatment of bone resorption disorders, their potential innocuousness makes them good candidates to control tropical diseases...
  39. ncbi Bisphosphonate inhibitors of Toxoplasma gondi growth: in vitro, QSAR, and in vivo investigations
    Yan Ling
    Laboratory of Molecular Parasitology, Department of Pathobiology and Center for Zoonoses Research, University of Illinois at Urbana Champaign, 2001 South Lincoln Avenue, Urbana, Illinois, 61802, USA
    J Med Chem 48:3130-40. 2005
    ..Overall, these results indicate that alkyl bisphosphonates are promising compounds for further development as agents against Toxoplasma gondii growth, in vivo...
  40. ncbi Bisphosphonates as inhibitors of Trypanosoma cruzi hexokinase: kinetic and metabolic studies
    Carlos E Sanz-Rodríguez
    Laboratorio de Quimica Biologica, Centro de Biofisica y Bioquimica, Instituto Venezolano de Investigaciones Cientificas, Caracas 1020, Venezuela
    J Biol Chem 282:12377-87. 2007
    ..Taken together, our results suggest that these novel bisphosphonates act primarily as specific inhibitors of TcHK and may represent a novel class of selective anti-T. cruzi agents...
  41. pmc Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases
    Rey Ting Guo
    Taiwan International Graduate Program, Institute of Biological Chemistry, Core Facility for Protein Crystallography, Academia Sinica, Taipei 115, Taiwan
    Proc Natl Acad Sci U S A 104:10022-7. 2007
    ....
  42. ncbi The farnesyl-diphosphate/geranylgeranyl-diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and a molecular target of bisphosphonates
    Yan Ling
    Department of Pathobiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Biol Chem 282:30804-16. 2007
    ....
  43. pmc Thermodynamics of bisphosphonates binding to human bone: a two-site model
    Sujoy Mukherjee
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Am Chem Soc 131:8374-5. 2009
    ..95 (a 0.19 kcal error variance estimate, approximately 3% of the total DeltaG range), opening up the way to designing novel chemotherapy, immunotherapy, and anti-infectious disease drugs having weak bone binding affinity...
  44. pmc Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results
    Yongcheng Song
    Department of Chemistry and Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Med Chem 52:3869-80. 2009
    ..Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections...
  45. pmc Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus
    Yongcheng Song
    Department of Chemistry, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Med Chem 52:976-88. 2009
    ..These results open up the way to developing potent and selective inhibitors of an important virulence factor in S. aureus, a major human pathogen...
  46. pmc Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation
    Yonghui Zhang
    Department of Chemistry, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Am Chem Soc 131:5153-62. 2009
    ....
  47. pmc Bisphosphonate inhibition of a Plasmodium farnesyl diphosphate synthase and a general method for predicting cell-based activity from enzyme data
    Dushyant Mukkamala
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
    J Med Chem 51:7827-33. 2008
    ..13). These results are of interest since they represent a general way to predict cell from enzyme inhibition data, with in three cases, R(2) values increasing from approximately 0.02 to 0.72...
  48. pmc Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation
    Cammy K-M Chen
    Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan
    J Med Chem 51:5594-607. 2008
    ....
  49. pmc Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR investigation
    Yongcheng Song
    Department of Chemistry, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, IL 61801, USA
    Bioorg Med Chem 16:8959-67. 2008
    ....
  50. pmc Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases
    Rong Cao
    Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    Proteins 73:431-9. 2008
    ..Overall, these results are of general interest since they show that some bisphosphonates can bind to more than one trans-prenyl synthase enzyme which, in some cases, can be expected to enhance their overall activity in vitro and in vivo...
  51. pmc A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence
    Chia I Liu
    Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan
    Science 319:1391-4. 2008
    ..This finding represents proof of principle for a virulence factor-based therapy against S. aureus...
  52. doi NMR investigations of the static and dynamic structures of bisphosphonates on human bone: a molecular model
    Sujoy Mukherjee
    Center for Biophysics and Computational Biology, 607 South Mathews Avenue, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Am Chem Soc 130:1264-73. 2008
    ....
  53. ncbi Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption
    John M Sanders
    Department of Chemistry, 600 South Mathews Avenue, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Med Chem 48:2957-63. 2005
    ..As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs...