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Antimicrobial Agents and Chemotherapy, August 2002, p. 2619-2626, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2619-2626.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Short-Chain Aliphatic Polysulfonates Inhibit the Entry of Plasmodium into Red Blood Cells

Robert Kisilevsky,^1* Ian Crandall,^2,3 Walter A. Szarek,⁴ Shridhar Bhat,⁴ Christopher Tan,⁴ Lee Boudreau,¹ and Kevin C. Kain^3,5

Department of Pathology, Queen's University, and The Syl and Molly Apps Research Center, Kingston General Hospital,¹ Department of Chemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6,⁴ Toronto Medical Laboratories,² Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 2C4,³ Institute of Medical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8⁵

Received 26 November 2001/ Returned for modification 21 December 2001/ Accepted 1 May 2002

Several steps in the pathogenesis of a Plasmodium falciparum infection depend on interactions of parasite surface proteins with negatively charged sugars on the surface of host cells such as sialate residues or glycosaminoglycans. For these reasons, our previous studies examining agents that interfere with heparan sulfate-protein binding during amyloidogenesis suggested that short-chain aliphatic polysulfonates may prove useful as antimalarial agents. A series of related polysulfonates were synthesized and assessed both in tissue culture with the asexual stages of P. falciparum in human red blood cells and in vivo by use of Plasmodium berghei infections in mice. Poly(vinylsulfonate sodium salt) (molecular weight range, 1,500 to 3,000) proved effective in interfering with P. falciparum merozoite entry into human red blood cells and significantly delaying the increase in the level of P. berghei parasitemia in mice. The concept that anionic molecules that mimic large polysaccharide structures may have antimalarial properties has been suggested and examined previously. Our results suggest that related anionic agents [poly(vinylsulfonate sodium salt)-like molecules] orders of magnitude smaller than those previously considered may prove useful in abrogating merozoite entry into erythrocytes and may potentially block sporozoite entry into liver cells. Structure-activity studies conducted to enhance these properties may provide compounds with scope for significant further analysis and development.

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* Corresponding author. Mailing address: Department of Pathology, Queen's University, Kingston, Ontario K7L 3N6, Canada. Phone: (613) 533-6411. Fax: (613) 533-2907. E-mail: Kisilevsky{at}cliff.path.queensu.ca.

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Antimicrobial Agents and Chemotherapy, August 2002, p. 2619-2626, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2619-2626.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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