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Antimicrobial Agents and Chemotherapy, February 2006, p. 724-730, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.724-730.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Rational Design of Anticytoadherence Inhibitors for Plasmodium falciparum Based on the Crystal Structure of Human Intercellular Adhesion Molecule 1

Matthias Dormeyer,¹ Yvonne Adams,^2, Bernd Kramer,¹ Srabasti Chakravorty,³ Man Tsuey Tse,^3, Stefano Pegoraro,¹ Lisa Whittaker,^3, Michael Lanzer,² and Alister Craig^3*

4SC AG, Am Klopferspitz 19a, D-82152 Martinsried, Germany,¹ Abteilung Parasitologie, Universitat Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany,² Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom³

Received 23 September 2005/ Returned for modification 22 October 2005/ Accepted 12 November 2005

Adhesion of Plasmodium falciparum-infected erythrocytes (IE) to host endothelium has been associated with pathology in malaria. Although the interaction with endothelial cells can be complex due to the relatively large number of host receptors available for binding, specific proteins have been identified that are more commonly used than others. For example, binding to intercellular adhesion molecule 1 (ICAM 1) is found frequently in parasites from pediatric cases of malaria. The binding site for P. falciparum-infected erythrocytes on ICAM 1 has been mapped in some detail and is distinct from the site for lymphocyte function-associated antigen 1 (LFA-1). Part of the ICAM 1 binding site for P. falciparum-infected erythrocytes (the DE loop) was used to screen a library of compounds based on its structure (derived from the crystal structure of human ICAM 1). This resulted in the identification of 36 structural mimeotopes as potential competitive inhibitors of binding. One of these compounds, (+)-epigalloyl-catechin-gallate [(+)-EGCG], was found to inhibit IE adhesion to ICAM 1 in a dose-dependent manner with two variant ICAM 1-binding parasite lines, providing the first example of a potential mimeotope-based anticytoadherence inhibitor for Plasmodium falciparum.

Present address: Clinical Tropical Medicine Laboratory, The Queensland Institute of Medical Research, P.O. Box Royal Brisbane Hospital, Infectious Diseases and Immunology Division, Herston, Qld 4029, Australia.

Present address: Centre for Drug Delivery Research, The School of Pharmacy, University of London, 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.

Present address: Cellular Pathophysiology Research Group, Department of Clinical Sciences, Duncan Building, University of Liverpool, Daulby Street, L69 3GA, United Kingdom.