title: Disrupting malaria parasite AMA1-RON2 interaction with a small molecule prevents erythrocyte invasion.
abstract: Plasmodium falciparum resistance to artemisinin derivatives, the first-line antimalarial drug, drives the search for new classes of chemotherapeutic agents. Current discovery is primarily directed against the intracellular forms of the parasite. However, late schizont-infected red blood cells (RBCs) may still rupture and cause disease by sequestration; consequently targeting invasion may reduce disease severity. Merozoite invasion of RBCs requires interaction between two parasite proteins AMA1 and RON2. Here we identify the first inhibitor of this interaction that also blocks merozoite invasion in genetically distinct parasites by screening a library of over 21,000 compounds. We demonstrate that this inhibition is mediated by the small molecule binding to AMA1 and blocking the formation of AMA1-RON complex. Electron microscopy confirms that the inhibitor prevents junction formation, a critical step in invasion that results from AMA1-RON2 binding. This study uncovers a strategy that will allow for highly effective combination therapies alongside existing antimalarial drugs.
authors.affiliation: Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852, USA. srinivasanp@niaid.nih.gov
authors.forename: Prakash
authors.initials: P
authors.lastname: Srinivasan
authors.forename: Adam
authors.initials: A
authors.lastname: Yasgar
authors.forename: Diane K
authors.initials: DK
authors.lastname: Luci
authors.forename: Wandy L
authors.initials: WL
authors.lastname: Beatty
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: John
authors.initials: J
authors.lastname: Andersen
authors.forename: David L
authors.initials: DL
authors.lastname: Narum
authors.forename: J Kathleen
authors.initials: JK
authors.lastname: Moch
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.forename: J David
authors.initials: JD
authors.lastname: Haynes
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology* / Q000648:ultrastructure; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000469:parasitology*; D052940:Merozoites / Q000187:drug effects / Q000648:ultrastructure; D010271:Parasites / Q000187:drug effects / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015800:Protozoan Proteins / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; C031327:artemisinin; D019061:src-Family Kinases
references.citation: J Biomol Screen. 1999;4(2):67-73
references.pmid: 10838414
references.citation: Curr Pharm Des. 2011;17(6):560-8
references.pmid: 21391906
references.citation: PLoS Pathog. 2011 Feb 10;7(2):e1001276
references.pmid: 21347343
references.citation: Nature. 2011 Aug 24;477(7364):344-8
references.pmid: 21866101
references.citation: Science. 2004 Feb 6;303(5659):844-8
references.pmid: 14704432
references.citation: PLoS Pathog. 2010 Feb 05;6(2):e1000746
references.pmid: 20140184
references.citation: Cell Host Microbe. 2011 Jan 20;9(1):9-20
references.pmid: 21238943
references.citation: Cell Host Microbe. 2011 Oct 20;10(4):410-9
references.pmid: 22018241
references.citation: Science. 1975 Feb 28;187(4178):748-50
references.pmid: 803712
references.citation: J Cell Biol. 1978 Apr;77(1):72-82
references.pmid: 96121
references.citation: Lancet. 2012 Feb 4;379(9814):413-31
references.pmid: 22305225
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12736-41
references.pmid: 16129835
references.citation: PLoS Pathog. 2012;8(6):e1002755
references.pmid: 22737069
references.citation: J Mol Biol. 1998 Jul 3;280(1):1-9
references.pmid: 9653027
references.citation: Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W265-9
references.pmid: 18539611
references.citation: Mol Microbiol. 2004 Apr;52(1):159-68
references.pmid: 15049818
references.citation: N Engl J Med. 2008 Dec 11;359(24):2619-20
references.pmid: 19064625
references.citation: Science. 2011 Jul 22;333(6041):463-7
references.pmid: 21778402
references.citation: Lancet. 2012 May 26;379(9830):1960-6
references.pmid: 22484134
references.citation: Biochemistry. 2001 Jun 19;40(24):7084-91
references.pmid: 11401553
references.citation: Proc Natl Acad Sci U S A. 1990 Apr;87(8):3018-22
references.pmid: 2183222
references.citation: Mol Cell. 2000 Oct;6(4):861-71
references.pmid: 11090624
references.citation: Nature. 1976 Oct 28;263(5580):767-9
references.pmid: 825784
references.citation: PLoS Pathog. 2009 Feb;5(2):e1000309
references.pmid: 19247437
references.citation: Annu Rev Pharmacol Toxicol. 2009;49:223-41
references.pmid: 18834305
references.citation: Infect Immun. 2005 Oct;73(10):6981-9
references.pmid: 16177378
references.citation: Infect Immun. 2002 Dec;70(12):6948-60
references.pmid: 12438374
references.citation: Nat Med. 2013 Feb;19(2):156-67
references.pmid: 23389616
references.citation: BMC Genomics. 2004 Oct 12;5:79
references.pmid: 15479470
references.citation: Bioorg Med Chem Lett. 2000 Oct 2;10(19):2167-70
references.pmid: 11012021
references.citation: Curr Genet. 2008 Nov;54(5):223-39
references.pmid: 18802698
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3784-9
references.pmid: 22355140
references.citation: Antimicrob Agents Chemother. 2005 Nov;49(11):4721-32
references.pmid: 16251317
references.citation: PLoS One. 2012;7(10):e46094
references.pmid: 23056238
references.citation: PLoS Pathog. 2009 Jan;5(1):e1000273
references.pmid: 19165323
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13275-80
references.pmid: 21788485
references.citation: Science. 1976 Aug 20;193(4254):673-5
references.pmid: 781840
references.citation: PLoS Pathog. 2012;8(4):e1002627
references.pmid: 22496653
references.citation: Mol Biochem Parasitol. 2010 Feb;169(2):71-8
references.pmid: 19800372
references.citation: Nat Chem Biol. 2009 Oct;5(10):765-71
references.pmid: 19734910