Suramin and suramin analogues inhibit merozoite surface protein-1 secondary processing and erythrocyte invasion by the malaria parasite Plasmodium falciparum

S L Fleck, B Birdsall, J Babon, A R Dluzewski, S R Martin, W D Morgan, E Angov, C A Kettleborough, J Feeney, M J Blackman, A A Holder

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51 Citations (Scopus)

Abstract

Malarial merozoites invade erythrocytes; and as an essential step in this invasion process, the 42-kDa fragment of Plasmodium falciparum merozoite surface protein-1 (MSP1(42)) is further cleaved to a 33-kDa N-terminal polypeptide (MSP1(33)) and an 19-kDa C-terminal fragment (MSP1(19)) in a secondary processing step. Suramin was shown to inhibit both merozoite invasion and MSP142 proteolytic cleavage. This polysulfonated naphthylurea bound directly to recombinant P. falciparum MSP1(42) (K-d = 0.2 muM) and to Plasmodium vivax MSP1(42) (K-d = 0.3 muM) as measured by fluorescence enhancement in the presence of the protein and by isothermal titration calorimetry. Suramin bound only slightly less tightly to the P. vivax MSP1(33) (K-d = 1.5 muM) secondary processing product ( fluorescence measurements), but very weakly to MSP1(19) (K-d similar to15 mM) (NMR measurements). Several residues in MSP1(19) were implicated in the interaction with suramin using NMR measurements. A series of symmetrical suramin analogues that differ in the number of aromatic rings and substitution patterns of the terminal naphthylamine groups was examined in invasion and processing assays. Two classes of analogue with either two or four bridging rings were found to be active in both assays, whereas two other classes without bridging rings were inactive. We propose that suramin and related compounds inhibit erythrocyte invasion by binding to MSP1 and by preventing its cleavage by the secondary processing protease. The results indicate that enzymatic events during invasion are suitable targets for drug development and validate the novel concept of an inhibitor binding to a macromolecular substrate to prevent its proteolysis by a protease.
Original languageEnglish
Pages (from-to)47670 - 47677
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number48
DOIs
Publication statusPublished - 28 Nov 2003

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