This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jiang, S.
Right arrow Articles by Kyle, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jiang, S.
Right arrow Articles by Kyle, D. E.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2001, p. 2577-2584, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2577-2584.2001

New Class of Small Nonpeptidyl Compounds Blocks Plasmodium falciparum Development In Vitro by Inhibiting Plasmepsins

Suping Jiang,1,* Sean T. Prigge,1 Lan Wei,1 Yu-e Gao,1 Thomas H. Hudson,1 Lucia Gerena,1 John B. Dame,2 and Dennis E. Kyle1

Department of Parasitology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500,1 and Department of Pathobiology, University of Florida, Gainesville, Florida 32611-08802

Received 4 October 2000/Returned for modification 5 December 2000/Accepted 4 June 2001

Malarial parasites rely on aspartic proteases called plasmepsins to digest hemoglobin during the intraerythrocytic stage. Plasmepsins from Plasmodium falciparum and Plasmodium vivax have been cloned and expressed for a variety of structural and enzymatic studies. Recombinant plasmepsins possess kinetic similarity to the native enzymes, indicating their suitability for target-based antimalarial drug development. We developed an automated assay of P. falciparum plasmepsin II and P. vivax plasmepsin to quickly screen compounds in the Walter Reed chemical database. A low-molecular-mass (346 Da) diphenylurea derivative (WR268961) was found to inhibit plasmepsins with a Ki of 1 to 6 µM. This compound appears to be selective for plasmepsin, since it is a poor inhibitor of the human aspartic protease cathepsin D (Ki greater than 280 µM). WR268961 inhibited the growth of P. falciparum strains W2 and D6, with 50% inhibitory concentrations ranging from 0.03 to 0.16 µg/ml, but was much less toxic to mammalian cells. The Walter Reed chemical database contains over 1,500 compounds with a diphenylurea core structure, 9 of which inhibit the plasmepsins, with Ki values ranging from 0.05 to 0.68 µM. These nine compounds show specificity for the plasmepsins over human cathepsin D, but they are poor inhibitors of P. falciparum growth in vitro. Computational docking experiments indicate how diphenylurea compounds bind to the plasmepsin active site and inhibit the enzyme.

* Corresponding author. Present address: Department of Immunology and Medicine, USA Medical Component, AFRIMS, APO AP 96546. Phone: (301) 319-9797. Fax: (301) 319-9954. E-mail: suping.jiang{at}na.amedd.army.mil.

Antimicrobial Agents and Chemotherapy, September 2001, p. 2577-2584, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2577-2584.2001


This article has been cited by other articles:

  • Prade, L., Jones, A. F., Boss, C., Richard-Bildstein, S., Meyer, S., Binkert, C., Bur, D. (2005). X-ray Structure of Plasmepsin II Complexed with a Potent Achiral Inhibitor. J. Biol. Chem. 280: 23837-23843 [Abstract] [Full Text]  
  • Baldwin, J., Michnoff, C. H., Malmquist, N. A., White, J., Roth, M. G., Rathod, P. K., Phillips, M. A. (2005). High-throughput Screening for Potent and Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase. J. Biol. Chem. 280: 21847-21853 [Abstract] [Full Text]  
  • Jiang, S., Zeng, Q., Gettayacamin, M., Tungtaeng, A., Wannaying, S., Lim, A., Hansukjariya, P., Okunji, C. O., Zhu, S., Fang, D. (2005). Antimalarial Activities and Therapeutic Properties of Febrifugine Analogs. Antimicrob. Agents Chemother. 49: 1169-1176 [Abstract] [Full Text]  
  • Liu, J., Gluzman, I. Y., Drew, M. E., Goldberg, D. E. (2005). The Role of Plasmodium falciparum Food Vacuole Plasmepsins. J. Biol. Chem. 280: 1432-1437 [Abstract] [Full Text]  
  • Omara-Opyene, A. L., Moura, P. A., Sulsona, C. R., Bonilla, J. A., Yowell, C. A., Fujioka, H., Fidock, D. A., Dame, J. B. (2004). Genetic Disruption of the Plasmodium falciparum Digestive Vacuole Plasmepsins Demonstrates Their Functional Redundancy. J. Biol. Chem. 279: 54088-54096 [Abstract] [Full Text]  
  • Rosenthal, P. J. (2003). Antimalarial drug discovery: old and new approaches. J. Exp. Biol. 206: 3735-3744 [Abstract] [Full Text]  
  • Marcinkeviciene, J., Kopcho, L. M., Yang, T., Copeland, R. A., Glass, B. M., Combs, A. P., Falahatpisheh, N., Thompson, L. (2002). Novel Inhibition of Porcine Pepsin by a Substituted Piperidine. PREFERENCE FOR ONE OF THE ENZYME CONFORMERS. J. Biol. Chem. 277: 28677-28682 [Abstract] [Full Text]  
  • Banerjee, R., Liu, J., Beatty, W., Pelosof, L., Klemba, M., Goldberg, D. E. (2002). Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc. Natl. Acad. Sci. USA 99: 990-995 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»