title: Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission.
abstract: Inhibiting Plasmodium development in mosquitoes will block malaria transmission. Fibrinogen-related protein 1 (FREP1) is critical for parasite infection in Anopheles gambiae and facilitates Plasmodium invasion in mosquitoes through interacting with gametocytes and ookinetes. To test the hypothesis that small molecules that disrupt this interaction will prevent parasites from infecting mosquitoes, we developed an ELISA-based method to screen a fungal extract library. We obtained a candidate fungal extract of Aspergillus niger that inhibited the interaction between FREP1 and P. falciparum infected cells by about 92%. The inhibition specificity was confirmed by immunofluorescence assays. Notably, feeding mosquitoes with the candidate fungal extract significantly inhibited P. falciparum infection in the midgut without cytotoxicity or inhibition of the development of P. falciparum gametocytes or ookinetes. A bioactive natural product that prevents FREP1 from binding to gametocytes or ookinetes was isolated and identified as P-orlandin. Importantly, the nontoxic orlandin significantly reduced P. falciparum infection intensity in mosquitoes. Therefore, disruption of the interaction between FREP1 and parasites effectively reduces Plasmodium infection in mosquitoes. Targeting FREP1 with small molecules is thus an effective novel approach to block malaria transmission.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Niu
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
authors.forename: Genwei
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
authors.forename: Jarrod B
authors.initials: JB
authors.lastname: King
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cichewicz
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000852:Anopheles / Q000187:drug effects / Q000469:parasitology; D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D001234:Aspergillus niger / Q000737:chemistry / Q000302:isolation & purification; D003001:Cloning, Molecular; D045424:Complex Mixtures / Q000737:chemistry; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007303:Insect Vectors / Q000187:drug effects / Q000469:parasitology; D008018:Life Cycle Stages / Q000187:drug effects* / Q000502:physiology; D016778:Malaria, Falciparum / Q000469:parasitology / Q000517:prevention & control* / Q000635:transmission; D009994:Osmolar Concentration; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012988:Soil Microbiology; D014468:Umbelliferones / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D045424:Complex Mixtures; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D014468:Umbelliferones; C019511:orlandin