Targeting Cysteine Proteases: Antiparasitic Chemotherapy

Summary

Principal Investigator: James McKerrow
Abstract: No Abstract Provided.
Funding Period: 1997-05-01 - 2010-05-31
more information: NIH RePORT

Top Publications

  1. pmc Mapping inhibitor binding modes on an active cysteine protease via nuclear magnetic resonance spectroscopy
    Gregory M Lee
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158 2280, USA
    Biochemistry 51:10087-98. 2012
  2. pmc Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit
    Chiung Kuang Chen
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, United States of America
    PLoS Negl Trop Dis 3:e372. 2009
  3. pmc Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity
    Iain D Kerr
    Department of Cellular and Molecular Pharmacology and Department of Pathology, University of California, San Francisco, California 94158, USA
    J Med Chem 52:852-7. 2009
  4. pmc The cathepsin L of Toxoplasma gondii (TgCPL) and its endogenous macromolecular inhibitor, toxostatin
    Robert Huang
    Department of Medicine, University of California, San Diego, CA 92103, United States
    Mol Biochem Parasitol 164:86-94. 2009
  5. ncbi Two approaches to discovering and developing new drugs for Chagas disease
    Jh McKerrow
    Sandler Center at Mission Bay, University of California, San Francisco, CA, USA, 94158 2330
    Mem Inst Oswaldo Cruz 104:263-9. 2009
  6. pmc A kernel for open source drug discovery in tropical diseases
    Leticia Ortí
    Structural Genomics Unit, Bioinformatics and Genomics Department, Centro de Investigacion Principe Felipe, Valencia, Spain
    PLoS Negl Trop Dis 3:e418. 2009
  7. pmc Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3
    Shoba Subramanian
    Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 4:e5156. 2009
  8. pmc Two approaches to discovering and developing new drugs for Chagas disease
    J H McKerrow
    Sandler Center at Mission Bay, University of California, San Francisco, CA 94158 2330, USA
    Mem Inst Oswaldo Cruz 104:263-9. 2009
  9. ncbi Antimalarial compounds from the stem bark of Vismia laurentii
    Diderot T Noungoue
    Department of Organic Chemistry, Faculty of Science, TWAS Research Unit TRU of University of Yaoundé I, P O Box 812, Yaounde, Cameroon
    Z Naturforsch C 64:210-4. 2009
  10. pmc Vinyl sulfones as antiparasitic agents and a structural basis for drug design
    Iain D Kerr
    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158 2550, USA
    J Biol Chem 284:25697-703. 2009

Detail Information

Publications74

  1. pmc Mapping inhibitor binding modes on an active cysteine protease via nuclear magnetic resonance spectroscopy
    Gregory M Lee
    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158 2280, USA
    Biochemistry 51:10087-98. 2012
    ..These results provide examples of how NMR spectroscopy can be used to screen compounds for fast evaluation of enzyme-inhibitor interactions to facilitate lead compound identification and subsequent structural studies...
  2. pmc Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit
    Chiung Kuang Chen
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, United States of America
    PLoS Negl Trop Dis 3:e372. 2009
    ..One potential new target for Chagas' disease chemotherapy is sterol 14alpha-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols...
  3. pmc Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity
    Iain D Kerr
    Department of Cellular and Molecular Pharmacology and Department of Pathology, University of California, San Francisco, California 94158, USA
    J Med Chem 52:852-7. 2009
    ..The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes...
  4. pmc The cathepsin L of Toxoplasma gondii (TgCPL) and its endogenous macromolecular inhibitor, toxostatin
    Robert Huang
    Department of Medicine, University of California, San Diego, CA 92103, United States
    Mol Biochem Parasitol 164:86-94. 2009
    ..These findings provide important insights into the proteolytic cascades of T. gondii and their endogenous control...
  5. ncbi Two approaches to discovering and developing new drugs for Chagas disease
    Jh McKerrow
    Sandler Center at Mission Bay, University of California, San Francisco, CA, USA, 94158 2330
    Mem Inst Oswaldo Cruz 104:263-9. 2009
    ..It is optimized for robotic liquid handling and has been validated through a screen of a library of FDA-approved drugs identifying 65 hits...
  6. pmc A kernel for open source drug discovery in tropical diseases
    Leticia Ortí
    Structural Genomics Unit, Bioinformatics and Genomics Department, Centro de Investigacion Principe Felipe, Valencia, Spain
    PLoS Negl Trop Dis 3:e418. 2009
    ..Historically, open source software collaborations have almost never succeeded without such "kernels"...
  7. pmc Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3
    Shoba Subramanian
    Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, California, United States of America
    PLoS ONE 4:e5156. 2009
    ..falciparum and with the possibility of developing small molecule inhibitors with optimized specificity as antimalarial agents...
  8. pmc Two approaches to discovering and developing new drugs for Chagas disease
    J H McKerrow
    Sandler Center at Mission Bay, University of California, San Francisco, CA 94158 2330, USA
    Mem Inst Oswaldo Cruz 104:263-9. 2009
    ..It is optimized for robotic liquid handling and has been validated through a screen of a library of FDA-approved drugs identifying 65 hits...
  9. ncbi Antimalarial compounds from the stem bark of Vismia laurentii
    Diderot T Noungoue
    Department of Organic Chemistry, Faculty of Science, TWAS Research Unit TRU of University of Yaoundé I, P O Box 812, Yaounde, Cameroon
    Z Naturforsch C 64:210-4. 2009
    ..The structure of all these compounds was elucidated by spectroscopic means. The stem bark extract and compounds 1 and 3 showed good antimalarial activity against the W2 strain of Plasmodium falciparum...
  10. pmc Vinyl sulfones as antiparasitic agents and a structural basis for drug design
    Iain D Kerr
    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158 2550, USA
    J Biol Chem 284:25697-703. 2009
    ....
  11. pmc Kinetoplastids: related protozoan pathogens, different diseases
    Ken Stuart
    Seattle Biomedical Research Institute, Seattle, Washington, USA
    J Clin Invest 118:1301-10. 2008
    ....
  12. pmc Experimental malaria infection triggers early expansion of natural killer cells
    Charles C Kim
    Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
    Infect Immun 76:5873-82. 2008
    ..These data indicate that the early response to P. chabaudi infection of the blood is marked by a primary wave of interferon with a subsequent response by NK cells...
  13. pmc Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB
    Jeremy P Mallari
    Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, CA 94143 2280, USA
    Bioorg Med Chem Lett 18:2883-5. 2008
    ..The activity of these compounds was determined against cultured T. brucei, and specificity was assessed with a panel of four mammalian cell lines...
  14. ncbi Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB
    Jeremy P Mallari
    Graduate Program in Chemistry and Chemical Biology and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143 2280, USA
    J Med Chem 51:545-52. 2008
    ..In addition, a predictive model of trypanocidal activity was developed on the basis of potency against TbcatB and various calculated physical property descriptors...
  15. pmc Rescoring docking hit lists for model cavity sites: predictions and experimental testing
    Alan P Graves
    Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158 2330, USA
    J Mol Biol 377:914-34. 2008
    ..We consider the origins of the successes and failures in MM-GBSA rescoring in these model cavity sites and the prospects for rescoring in biologically relevant targets...
  16. pmc Identification of the major cysteine protease of Giardia and its role in encystation
    Kelly N DuBois
    Department of Pathology, the Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, CA 94158, USA
    J Biol Chem 283:18024-31. 2008
    ..These data suggest that Giardia cysteine protease 2 is not only the major cysteine endoprotease expressed in Giardia, but is also central to the encystation process...
  17. pmc A contiguous compartment functions as endoplasmic reticulum and endosome/lysosome in Giardia lamblia
    Marla Abodeely
    Department of Pathology, the Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, CA 94158, USA
    Eukaryot Cell 8:1665-76. 2009
    ..This system also may have functional similarity to the retrograde transport of toxins and major histocompatibility complex class I function in the ER of mammals...
  18. ncbi Synthesis and evaluation of non-peptidic cysteine protease inhibitors of P. falciparum derived from etacrynic acid
    Marie Adrienne Dude
    Research Center for Infectious Diseases, University of Wurzburg, Rontgenring 11, 97070 Wurzburg, Germany
    Molecules 14:19-35. 2009
    ..The two most active compounds of the series displayed IC(50) values of 9.0 and 18.8 microM against Plasmodia...
  19. pmc Imidazoquines as antimalarial and antipneumocystis agents
    Nuno Vale
    Departamento de Quimica, Faculdade de Ciencias, Centro de Investigação em Química da Universidade do Porto, Universidade do Porto, Rua do Campo Alegre 687, P 4169 007 Porto, Portugal
    J Med Chem 52:7800-7. 2009
    ....
  20. pmc Drug discovery for neglected tropical diseases at the Sandler Center
    Stephanie A Robertson
    Sandler Center for Drug Discovery, Department of Pharmaceutical Chemistry, University of California, 600 16th Street, S 272, San Francisco, CA 94158, USA
    Future Med Chem 3:1279-88. 2011
    ..Our approach is akin to drug repurposing, except that we seek to repurpose leads rather than drugs. Medicinal chemistry can then be applied to optimize the leads specifically for the desired antiparasitic indication...
  21. pmc The Trypanosoma cruzi protease cruzain mediates immune evasion
    Patricia S Doyle
    Tropical Disease Research Unit and Sandler Center for Drug Discovery, Department of Pathology, University of California, San Francisco, California, United States of America
    PLoS Pathog 7:e1002139. 2011
    ..These early events allow T. cruzi survival and replication, and may lead to the spread of infection in acute Chagas' disease...
  22. ncbi Potent antiplasmodial extracts from Cameroonian Annonaceae
    Fabrice Fekam Boyom
    Laboratory of Phytobiochemistry and Medicinal Plants Study, Faculty of Science, University of Yaounde I, P O Box 812, Yaounde, Cameroon
    J Ethnopharmacol 134:717-24. 2011
    ....
  23. pmc The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion
    Ryan K Swenerton
    Department of Pathology, Sandler Center for Drug Discovery, University of California, San Francisco, California 94158, USA
    J Biol Chem 286:429-40. 2011
    ..Additionally, these OPB(-/-) parasites displayed decreased virulence in the murine footpad infection model...
  24. pmc Biochemical properties of a novel cysteine protease of Plasmodium vivax, vivapain-4
    Byoung Kuk Na
    Department of Molecular Parasitology and Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
    PLoS Negl Trop Dis 4:e849. 2010
    ..Two cysteine proteases, vivapain (VX)-2 and VX-3 have been characterized in P. vivax, but comprehensive studies of P. vivax cysteine proteases remain elusive...
  25. pmc Binding-site assessment by virtual fragment screening
    Niu Huang
    National Institute of Biological Sciences, Beijing, Beijing, China
    PLoS ONE 5:e10109. 2010
    ....
  26. pmc Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei
    Iain D Kerr
    Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America
    PLoS Negl Trop Dis 4:e701. 2010
    ..Of considerable interest is the exploration of these two enzymes as targets for cysteine protease inhibitors that are effective against T. brucei...
  27. pmc Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole
    Chiung Kuang Chen
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California, United States of America
    PLoS Negl Trop Dis 4:e651. 2010
    ..However, modification of azoles to enhance efficacy and circumvent potential drug resistance has been problematic for both parasitic and fungal infections due to the lack of structural insights into drug binding...
  28. pmc Antimalarial activity of azadipeptide nitriles
    Reik Löser
    Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Bioorg Med Chem Lett 20:252-5. 2010
    ..These first generation azadipeptide nitriles represent a promising new class of compounds for antimalarial drug development...
  29. ncbi Design, synthesis, and development of novel guaianolide-endoperoxides as potential antimalarial agents
    Lingzhi Sun
    Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi 38677, USA
    J Med Chem 53:7864-8. 2010
    ..Furthermore, SAR trends in thaperoxide analogues are presented and explained with the help of docking studies in the homology model of PfSERCA(PfATP6)...
  30. pmc Chemical genetics of Plasmodium falciparum
    W Armand Guiguemde
    Department of Chemical Biology and Therapeutics, St Jude Children s Research Hospital, Memphis, Tennessee 38105, USA
    Nature 465:311-5. 2010
    ..falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery...
  31. pmc Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy
    Katrien Brak
    Department of Chemistry, University of California, Berkeley, California 94720 1460, USA
    J Med Chem 53:1763-73. 2010
    ..These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy...
  32. pmc Automated site preparation in physics-based rescoring of receptor ligand complexes
    Chaya S Rapp
    Department of Chemistry, Stern College for Women, Yeshiva University, New York, New York 10016, USA
    Proteins 77:52-61. 2009
    ..7 to 1.5 A when applying ICDA. Large improvements are seen for specific classes of binding sites with titratable groups, such as aspartyl proteases...
  33. ncbi Antiplasmodial activity of extracts from seven medicinal plants used in malaria treatment in Cameroon
    Fabrice Fekam Boyom
    Laboratory of Phytobiochemistry and Medicinal Plants Study, Faculty of Science, University of Yaounde I, P O Box 812, Yaounde, Cameroon
    J Ethnopharmacol 123:483-8. 2009
    ..We have also explored the inhibition of the Plasmodium falciparum cysteine protease Falcipain-2...
  34. pmc Structure-guided development of selective TbcatB inhibitors
    Jeremy P Mallari
    Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94143 2280, USA
    J Med Chem 52:6489-93. 2009
    ..These data chemically validate TbcatB as a drug target and demonstrate that it is possible to potently and selectively inhibit TbcatB relative to trypanosomal and human homologues...
  35. ncbi Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes
    Priyadarshini Jaishankar
    Small Molecule Discovery Center, University of California, San Francisco, CA 94158, USA
    Bioorg Med Chem Lett 18:624-8. 2008
    ..Rhodesain selectivity could be enhanced further by combining these P2 modifications with certain P3 amide substituents...
  36. pmc Synthesis of macrocyclic trypanosomal cysteine protease inhibitors
    Yen Ting Chen
    Department of Chemistry, Scripps Florida, 5353 Parkside Drive, RE 2, Jupiter, FL 33458, USA
    Bioorg Med Chem Lett 18:5860-3. 2008
    ..Vinyl sulfone-containing macrocycles were synthesized via olefin ring-closing metathesis and evaluated against cruzain and the closely related cysteine protease, rhodesain...
  37. ncbi Synthesis and biological evaluation of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives against the cysteine protease falcipain-2 and a chloroquine resistant strain of Plasmodium falciparum
    Alex Chipeleme
    Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
    Bioorg Med Chem 15:273-82. 2007
    ..07microM against W2. Compound 8f also weakly inhibited falcipain-2, with an IC(50) of 3.16microM, although its principal antiparasitic activity did not appear to be due to inhibition of this enzyme...
  38. ncbi Falcipain cysteine proteases require bipartite motifs for trafficking to the Plasmodium falciparum food vacuole
    Shoba Subramanian
    Department of Medicine, Division of Infectious Disease, University of California, San Francisco, San Francisco, California 94143, USA
    J Biol Chem 282:24961-9. 2007
    ....
  39. pmc Host pathogen protein interactions predicted by comparative modeling
    Fred P Davis
    Department of Biopharmaceutical Sciences, University of California at San Francisco, San Francisco, California 94158, USA
    Protein Sci 16:2585-96. 2007
    ..Our computational method provides a means to mine whole-genome data and is complementary to experimental efforts in elucidating networks of host-pathogen protein interactions...
  40. pmc Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease
    Stephanie X Wang
    Department of Pathology and the Sandler Center, San Francisco General Hospital, University of California, CA 94143, USA
    Proc Natl Acad Sci U S A 103:11503-8. 2006
    ..Motifs similar to FP2(nose) and FP2(arm) are found only in related plasmodial proteases, suggesting that they confer malaria-specific functions...
  41. ncbi Proteases in parasitic diseases
    James H McKerrow
    Department of Pathology, Sandler Center, University of California, San Francisco, California 94143, USA
    Annu Rev Pathol 1:497-536. 2006
    ....
  42. pmc Protein complex compositions predicted by structural similarity
    Fred P Davis
    Department of Biopharmaceutical Sciences, California Institute for Quantitative Biomedical Research, University of California San Francisco, 1700 4th Street, Byers Hall, San Francisco, CA 94143 2552, USA
    Nucleic Acids Res 34:2943-52. 2006
    ..cerevisiae will contribute to expansion of the structural and functional coverage of protein interaction space. The predicted complexes are deposited in MODBASE (http://salilab.org/modbase)...
  43. ncbi Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers
    Taha Rezai
    Department of Chemistry and Biochemistry, University of California, Santa Cruz, 95064, USA
    J Am Chem Soc 128:2510-1. 2006
    ..The most permeable diastereomer, cyclo[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to that of the orally available drug cyclosporine A...
  44. ncbi Plasmodium falciparum: biochemical characterization of the cysteine protease falcipain-2'
    Naresh Singh
    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143 0811, USA
    Exp Parasitol 112:187-92. 2006
    ....
  45. ncbi Drug discovery and development for neglected parasitic diseases
    Adam R Renslo
    Department of Pharmaceutical Chemistry and the Small Molecule Discovery Center, University of California San Francisco, San Francisco, CA 94158, USA
    Nat Chem Biol 2:701-10. 2006
    ..These neglected diseases present unique challenges to drug development that are being addressed by new consortia of scientists from academia and industry...
  46. ncbi Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities
    Youngchool Choe
    Department of Pharmaceutical Chemistry, University of California at San Francisco, California 94143, USA
    J Biol Chem 281:12824-32. 2006
    ..This approach provides useful information for developing selective chemical probes to study protease-related pathologies and physiologies...
  47. ncbi Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides
    Taha Rezai
    Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
    J Am Chem Soc 128:14073-80. 2006
    ....
  48. pmc Localization of binding sites in protein structures by optimization of a composite scoring function
    Andrea Rossi
    Department of Biopharmaceutical Sciences and Pharmaceutical Chemistry, California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 94143 2552, USA
    Protein Sci 15:2366-80. 2006
    ..The method is completely automated (http://salilab.org/patcher) and can be applied on a large scale in a structural genomics setting...
  49. ncbi Antitrypanosomal activity of 5'-deoxy-5'-(iodomethylene)adenosine and related 6-N-cyclopropyladenosine analogues
    Magdalena Rapp
    Department of Chemistry and Biochemistry, Florida International University, Miami, Florida 33199, USA
    J Med Chem 49:2096-102. 2006
    ..In contrast to some other adenosine analogues modified at C5', the 6-N-cyclopropyladenosine analogues described here do not exhibit an inhibitory effect on AdoHcy hydrolase and displayed only marginal antiviral activity...
  50. pmc Falstatin, a cysteine protease inhibitor of Plasmodium falciparum, facilitates erythrocyte invasion
    Kailash C Pandey
    Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA
    PLoS Pathog 2:e117. 2006
    ..This mechanism of regulation of proteolysis suggests new strategies for the development of antimalarial agents that specifically disrupt erythrocyte invasion...
  51. ncbi Physics-based scoring of protein-ligand complexes: enrichment of known inhibitors in large-scale virtual screening
    Niu Huang
    Department of Pharmaceutical Chemistry, University of California San Francisco, Genentech Hall, 94143 2240, USA
    J Chem Inf Model 46:243-53. 2006
    ..We also present anecdotal but encouraging results assessing the ability of the rescoring method to predict specificity of inhibitors for structurally related proteins...
  52. ncbi Discovery of trypanocidal compounds by whole cell HTS of Trypanosoma brucei
    Zachary B Mackey
    Department of Pathology and the Sandler Center for Basic Research in Parasitic Diseases, University of California, QB3 1700 4th St, San Francisco, CA 94158, USA
    Chem Biol Drug Des 67:355-63. 2006
    ..These included the two approved trypanocidal drugs, suramin and pentamidine, several other drugs suspected but never validated as trypanocidal, and 17 novel trypanocidal drugs...
  53. ncbi Synthesis and evaluation of sulfonylurea derivatives as novel antimalarials
    Caritza Leon
    Laboratorio de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela, Caracas 1051, Venezuela
    Eur J Med Chem 42:735-42. 2007
    ..Indeed, these compounds may act against malaria parasites through multiple mechanisms...
  54. ncbi Physics-based methods for studying protein-ligand interactions
    Niu Huang
    Department of Pharmaceutical Chemistry, University of California San Francisco, 600 16th Street, San Francisco, CA 94158 2517, USA
    Curr Opin Drug Discov Devel 10:325-31. 2007
    ..Future directions for further improving current physics-based methods are also discussed...
  55. pmc A cysteine protease inhibitor cures Chagas' disease in an immunodeficient-mouse model of infection
    Patricia S Doyle
    Department of Pathology, University of California San Francisco, CA 94121, USA
    Antimicrob Agents Chemother 51:3932-9. 2007
    ..The majority (60 to 100%) of inhibitor-treated Rag1(-/-) mice had increased survival, negative PCR, and normal tissues by histopathological examination...
  56. ncbi Metal compounds for the treatment of parasitic diseases
    Simon P Fricker
    Genzyme Corporation, 49 New York Avenue, P O Box 9322, Framingham, MA 01701 9322, USA
    J Inorg Biochem 102:1839-45. 2008
    ..In conclusion this preliminary data indicates that metal complexes targeted at parasite cysteine proteases show promise for the treatment of both Chagas' disease and leishmaniasis...
  57. pmc RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model
    Maha Hamadien Abdulla
    Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biomedical Research, University of California San Francisco, San Francisco, California, USA
    PLoS Negl Trop Dis 2:e298. 2008
    ..Taken together, the data suggest that while TbCatB is the more likely target for the development of new chemotherapy, a possible role for brucipain is in facilitating parasite entry into the brain...
  58. pmc Development of protease inhibitors for protozoan infections
    James H McKerrow
    Department of Pathology, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158 2330, USA
    Curr Opin Infect Dis 21:668-72. 2008
    ..These roles include processing of host or parasite surface proteins for invasion of host cells, digestion of host proteins for nutrition, and inactivation of host immune defense mediators...
  59. pmc A parasite cysteine protease is key to host protein degradation and iron acquisition
    Theresa C O'Brien
    Department of Pathology and Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California 94158 2550, USA
    J Biol Chem 283:28934-43. 2008
    ..Because even a modest deficiency in tbcatB is lethal for the parasite, tbcatB is a logical target for the development of new anti-trypanosomal chemotherapy...
  60. pmc Identification of a new class of nonpeptidic inhibitors of cruzain
    Katrien Brak
    Department of Chemistry, University of California, Berkeley, California 94720, USA
    J Am Chem Soc 130:6404-10. 2008
    ..This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemotherapeutics for Chagas disease...
  61. ncbi Anti-plasmodial activity of some constituents of the root bark of Harungana madagascariensis LAM. (Hypericaceae)
    Bruno Ndjakou Lenta
    Department of Chemistry, Higher Teachers Training College, University of Yaounde 1, Yaounde, Cameroon
    Chem Pharm Bull (Tokyo) 55:464-7. 2007
    ..All the compounds were found to be active against the Plasmodium parasites with bazouanthrone (1) showing particular potency (IC50=1.80 microM)...
  62. ncbi Cathepsin Cs are key for the intracellular survival of the protozoan parasite, Toxoplasma gondii
    Xuchu Que
    Department of Pathology, University of California, San Diego, California 92103 8416, USA
    J Biol Chem 282:4994-5003. 2007
    ..gondii in the chick embryo model of toxoplasmosis. Thus, cathepsin Cs are critical to T. gondii growth and differentiation, and their unique specificities could be exploited to develop novel chemotherapeutic agents...
  63. ncbi An atomistic model of passive membrane permeability: application to a series of FDA approved drugs
    Chakrapani Kalyanaraman
    Department of Pharmaceutical Chemistry, UCSF, San Francisco, CA 94158 2517, USA
    J Comput Aided Mol Des 21:675-9. 2007
    ..We compare the computational results to previously published experimental PAMPA and Caco-2 permeabilities...
  64. pmc Proteomic analysis of adult S. mansoni gut contents
    Melaine Delcroix
    Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biomedical Research QB3, 1700 4th St, University of California, San Francisco, CA 94158 2330, USA
    Mol Biochem Parasitol 154:95-7. 2007
  65. ncbi Screening of protease inhibitors as antiplasmodial agents. Part I: Aziridines and epoxides
    Franziska Schulz
    Institute of Pharmacy and Food Chemistry, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany
    ChemMedChem 2:1214-24. 2007
    ..25-39.8 microM). As the compounds also display in vitro activity against the P. falciparum parasite in the submicromolar and low micromolar range, these compound classes are leads for new antiplasmodial falcipain inhibitors...
  66. pmc Bis-acridines as lead antiparasitic agents: structure-activity analysis of a discrete compound library in vitro
    Conor R Caffrey
    Sandler Center for Basic Research in Parasitic Diseases, BH508, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158 2330, USA
    Antimicrob Agents Chemother 51:2164-72. 2007
    ..Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization...
  67. ncbi A phagocytosis mutant of Entamoeba histolytica is less virulent due to deficient proteinase expression and release
    Ken K Hirata
    Departments of Pathology and Medicine, University of California, San Diego, CA 92103 8416, USA
    Exp Parasitol 115:192-9. 2007
    ..These findings provide an important link between phagocytosis, passive release of multiple cysteine proteinases, and attenuated virulence of this E. histolytica mutant...
  68. ncbi The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family
    Stephanie X Wang
    Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
    Structure 15:535-43. 2007
    ..Interactions of chagasin with a target protease are reminiscent of the cystatin family inhibitors. Protein inhibitors of cysteine proteases may have evolved more than once on nonhomologous scaffolds...
  69. pmc Use of recombinant Entamoeba histolytica cysteine proteinase 1 to identify a potent inhibitor of amebic invasion in a human colonic model
    Samuel G Melendez-Lopez
    Department of Pathology, University of California, San Diego, San Diego, California 92103 8416, USA
    Eukaryot Cell 6:1130-6. 2007
    ..The resultant dramatic inhibition of invasion by both inhibitors in this human colonic model of amebiasis strongly suggests a significant role of secreted amebic proteinases, such as EhCP1, in the pathogenesis of amebiasis...
  70. ncbi Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus
    D H Goetz
    Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA
    Biochemistry 46:8744-52. 2007
    ..These data provide the foundation for a rational small-molecule inhibitor design effort based upon the inhibitor scaffold identified, the crystal structure of the complex, and a more complete understanding of P1-P4 substrate specificity...
  71. ncbi Transcriptional and secretory responses of Entamoeba histolytica to mucins, epithelial cells and bacteria
    Anjan Debnath
    Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, San Francisco, CA 94158, USA
    Int J Parasitol 37:897-906. 2007
    ..The enhanced expression of this gene cluster is consistent with enhanced phagocytosis of E. histolytica during interaction with bacteria...
  72. ncbi Molecular mechanics methods for predicting protein-ligand binding
    Niu Huang
    Department of Pharmaceutical Chemistry, University of California San Francisco, UCSF MC 2240, Genentech Hall, Room N472C, 600 16th St, San Francisco, CA 94158 2517, USA
    Phys Chem Chem Phys 8:5166-77. 2006
    ..Future directions for further improving our physics-based scoring method are also discussed...