title: The antimalarial natural product symplostatin 4 is a nanomolar inhibitor of the food vacuole falcipains.
abstract: The marine natural product symplostatin 4 (Sym4) has been recognized as a potent antimalarial agent. However, its mode of action and, in particular, direct targets have to date remained elusive. We report a chemical synthesis of Sym4 and show that Sym4-treatment of P. falciparum-infected red blood cells (RBCs) results in the generation of a swollen food vacuole phenotype and a reduction of parasitemia at nanomolar concentrations. We furthermore demonstrate that Sym4 is a nanomolar inhibitor of the P. falciparum falcipains in infected RBCs, suggesting inhibition of the hemoglobin degradation pathway as Sym4's mode of action. Finally, we reveal a critical influence of the unusual methyl-methoxypyrrolinone (mmp) group of Sym4 for potent inhibition, indicating that Sym4 derivatives with such a mmp moiety might represent viable lead structures for the development of antimalarial falcipain inhibitors.
authors.affiliation: Zentrum für Medizinische Biotechnologie, Fakultät für Biologie, Universität Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany.
authors.forename: Sara Christina
authors.initials: SC
authors.lastname: Stolze
authors.forename: Edgar
authors.initials: E
authors.lastname: Deu
authors.forename: Farnusch
authors.initials: F
authors.lastname: Kaschani
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Florea
authors.forename: Kerstin H
authors.initials: KH
authors.lastname: Richau
authors.forename: Tom
authors.initials: T
authors.lastname: Colby
authors.forename: Renier A L
authors.initials: RA
authors.lastname: van der Hoorn
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004912:Erythrocytes / Q000469:parasitology*; D006454:Hemoglobins / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology
chemical_list: D000962:Antimalarials; D023181:Antimicrobial Cationic Peptides; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D010455:Peptides; C534687:gallinamide A; D003546:Cysteine Endopeptidases; C099607:falcipain