From (+)-epigallocatechin gallate to a simplified synthetic analogue as a cytoadherence inhibitor for P. falciparum

Gemma, Sandra, Brogi, Simone, Patil, Pradeep R., Giovani, Simone, Lamponi, Stefania, Cappelli, Andrea, Novellino, Ettore, Brown, Alan, Higgins, Matthew K., Mustaffa, Khairul, Szestak, Tadge, Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164, Campiani, Giuseppe, Butini, Stefania and Brindisi, Margherita (2013) 'From (+)-epigallocatechin gallate to a simplified synthetic analogue as a cytoadherence inhibitor for P. falciparum'. RSC Advances, Vol 4, Issue 9, pp. 4769-4781.

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Abstract

Parasite derived surface antigen PfEMP1 is a virulence factor of the human malaria parasite. PfEMP1 variants have been implicated in the cytoadherence of P. falciparum infected erythrocytes (iRBC) to several binding receptors on host vascular endothelium. Among them, binding to ICAM-1 seems to be related to severe manifestations of the disease such as cerebral malaria. The binding site for iRBC has been mapped to the BED-side of the N-terminal immunoglobulin-like domain of ICAM-1, and the DE-loop appears to be critical for binding. To date (+)-EGCG is the unique small molecule anti-cytoadherence inhibitor probably mimicking the DE-loop of ICAM-1. Here we report the discovery of a tetrahydroisoquinoline derivative, a prototype of a novel class of cytoadherence inhibitors, and an analogue of the natural compound characterized by a synthetically accessible scaffold. Molecular modeling analysis of (+)-EGCG and its synthetic tetrahydroisoquinoline analogue rationalized their binding mode to PfEMP1, confirming their ability to mimic the DE-loop.

Item Type:	Article
Subjects:	QS Anatomy > Histology > QS 532.5.E7 Epithelium QU Biochemistry > Cells and Genetics > QU 350 Cellular structures QU Biochemistry > Proteins. Amino Acids. Peptides > QU 58.5 DNA. QX Parasitology > Protozoa > QX 135 Plasmodia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1039/c3ra45933k
Depositing User:	Mary Creegan
Date Deposited:	24 Apr 2014 10:59
Last Modified:	17 Jul 2019 14:14
URI:	https://archive.lstmed.ac.uk/id/eprint/3667

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