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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


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