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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.

Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Volume50
Issue number2
Pages (from-to)724-730
Number of pages7
ISSN0066-4804
DOIs
Publication statusPublished - Feb 2006

ID: 340559273