title: A class of tricyclic compounds blocking malaria parasite oocyst development and transmission.
abstract: Malaria is a deadly infectious disease in many tropical and subtropical countries. Previous efforts to eradicate malaria have failed, largely due to the emergence of drug-resistant parasites, insecticide-resistant mosquitoes and, in particular, the lack of drugs or vaccines to block parasite transmission. ATP-binding cassette (ABC) transporters are known to play a role in drug transport, metabolism, and resistance in many organisms, including malaria parasites. To investigate whether a Plasmodium falciparum ABC transporter (Pf14_0244 or PfABCG2) modulates parasite susceptibility to chemical compounds or plays a role in drug resistance, we disrupted the gene encoding PfABCG2, screened the recombinant and the wild-type 3D7 parasites against a library containing 2,816 drugs approved for human or animal use, and identified an antihistamine (ketotifen) that became less active against the PfABCG2-disrupted parasite in culture. In addition to some activity against asexual stages and gametocytes, ketotifen was highly potent in blocking oocyst development of P. falciparum and the rodent parasite Plasmodium yoelii in mosquitoes. Tests of structurally related tricyclic compounds identified additional compounds with similar activities in inhibiting transmission. Additionally, ketotifen appeared to have some activity against relapse of Plasmodium cynomolgi infection in rhesus monkeys. Further clinical evaluation of ketotifen and related compounds, including synthetic new derivatives, in blocking malaria transmission may provide new weapons for the current effort of malaria eradication.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Eastman
authors.forename: Sittiporn
authors.initials: S
authors.lastname: Pattaradilokrat
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Raj
authors.forename: Saurabh
authors.initials: S
authors.lastname: Dixit
authors.forename: Bingbing
authors.initials: B
authors.lastname: Deng
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Takeshi Q
authors.initials: TQ
authors.lastname: Tanaka
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Hongying
authors.initials: H
authors.lastname: Jiang
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Kim C
authors.initials: KC
authors.lastname: Williamson
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Lambert
authors.forename: Carole
authors.initials: C
authors.lastname: Long
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wu
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D058492:Drug Repositioning; D057166:High-Throughput Screening Assays; D006801:Humans; D007665:Ketotifen / Q000031:analogs & derivatives / Q000494:pharmacology*; D008253:Macaca mulatta; D008288:Malaria / Q000378:metabolism / Q000469:parasitology / Q000517:prevention & control* / Q000635:transmission; D016778:Malaria, Falciparum / Q000378:metabolism / Q000469:parasitology / Q000517:prevention & control* / Q000635:transmission; D051379:Mice; D033661:Oocysts / Q000187:drug effects* / Q000254:growth & development; D016789:Plasmodium cynomolgi / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D010967:Plasmodium yoelii / Q000187:drug effects* / Q000254:growth & development; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D018926:Anti-Allergic Agents; D000962:Antimalarials; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; D007665:Ketotifen