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Rational design of anticytoadherence inhibitors for Plasmodium falciparum based on the crystal structure of human intercellular adhesion molecule 1

Dormeyer, M., Adams, Y., Kramer, B., Chakravorty, S., Tse, M.T., Pegoraro, S., Whittaker, Lisa, Lanzer, M. and Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164 (2006) 'Rational design of anticytoadherence inhibitors for Plasmodium falciparum based on the crystal structure of human intercellular adhesion molecule 1'. Antimicrobial Agents and Chemotherapy, Vol 50, Issue 2, pp. 724-730.

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Abstract

Adhesion of Plasmodium falciparunt-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 I 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 I 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.

Item Type: Article
Subjects: QX Parasitology > Protozoa > QX 135 Plasmodia
QZ Pathology > QZ 4 General works
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 150 Erythrocytes
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1128/AAC.50.2.724-730.2006
Depositing User: Sarah Lewis-Newton
Date Deposited: 07 Mar 2011 14:16
Last Modified: 17 Jul 2019 14:13
URI: https://archive.lstmed.ac.uk/id/eprint/1479

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