Rational Design of Anticytoadherence Inhibitors forPlasmodium falciparumBased on the Crystal Structure of Human Intercellular Adhesion Molecule 1

Dormeyer, Matthias; Adams, Yvonne; Kramer, Bernd; Chakravorty, Srabasti; Tse, Man Tsuey; Pegoraro, Stefano; Whittaker, Lisa; Lanzer, Michael; Craig, Alister

Abstract

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.

Citation

Dormeyer, M., Adams, Y., Kramer, B., Chakravorty, S., Tse, M. T., Pegoraro, S., …Craig, A. (2006). Rational Design of Anticytoadherence Inhibitors forPlasmodium falciparumBased on the Crystal Structure of Human Intercellular Adhesion Molecule 1. Antimicrobial Agents and Chemotherapy, 50(2), 724-730. https://doi.org/10.1128/aac.50.2.724-730.2006

• Journal Article Type: Article
• Acceptance Date: Nov 12, 2005
• Online Publication Date: Feb 1, 2006
• Publication Date: 2006-02
• Deposit Date: May 14, 2024
• Journal: Antimicrobial Agents and Chemotherapy
• Print ISSN: 0066-4804
• Electronic ISSN: 1098-6596
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 50
• Issue: 2
• Pages: 724-730
• DOI: https://doi.org/10.1128/aac.50.2.724-730.2006
• Public URL: https://keele-repository.worktribe.com/output/827458
• Additional Information: Received: 2005-09-23; Accepted: 2005-11-12; Published: 2006-02-01