Rational design of anticytoadherence inhibitors for Plasmodium falciparum based on the crystal structure of human intercellular adhesion molecule 1.
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.
Dormeyer
Matthias
M
4SC AG, Am Klopferspitz 19a, D-82152 Martinsried, Germany.
Adams
Yvonne
Y
Kramer
Bernd
B
Chakravorty
Srabasti
S
Tse
Man Tsuey
MT
Pegoraro
Stefano
S
Whittaker
Lisa
L
Lanzer
Michael
M
Craig
Alister
A
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001665:Binding Sites; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D003460:Crystallization; D015195:Drug Design; D004912:Erythrocytes / Q000469:parasitology / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects*
D000962:Antimalarials; D018799:Intercellular Adhesion Molecule-1; D002392:Catechin; C045651:epigallocatechin gallate