title: A combination of new screening assays for prioritization of transmission-blocking antimalarials reveals distinct dynamics of marketed and experimental drugs.
abstract: OBJECTIVE
  The development of drugs to reduce malaria transmission is an important part of malaria eradication plans. We set out to develop and validate a combination of new screening assays for prioritization of transmission-blocking molecules.
  
  
  METHODS
  We developed high-throughput assays for screening compounds against gametocytes, the parasite stages responsible for onward transmission to mosquitoes. An existing gametocyte parasitic lactate dehydrogenase (pLDH) assay was adapted for use in 384-well plates, and a novel homogeneous immunoassay to monitor the functional transition of female gametocytes into gametes was developed. A collection of 48 marketed and experimental antimalarials was screened and subsequently tested for impact on sporogony in Anopheles mosquitoes, to directly quantify the transmission-blocking properties of antimalarials in relation to their effects on gametocyte pLDH activity or gametogenesis.
  
  
  CONCLUSIONS
  The novel screening assays revealed distinct stage-specific kinetics and dynamics of drug effects. Peroxides showed the most potent transmission-blocking effects, with an intermediate speed of action and IC50 values that were 20-40-fold higher than the IC50s against the asexual stages causing clinical malaria. Finally, the novel synthetic peroxide OZ439 appeared to be a promising drug candidate as it exerted gametocytocidal and transmission-blocking effects at clinically relevant concentrations.
authors: TropIQ Health Sciences, Geert Grooteplein 28, huispost 268, 6525 GA, Nijmegen, The Netherlands.
authors: J M
authors: JM
authors: Bolscher
authors: TropIQ Health Sciences, Geert Grooteplein 28, huispost 268, 6525 GA, Nijmegen, The Netherlands.
authors: K M J
authors: KM
authors: Koolen
authors: Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors: G J
authors: GJ
authors: van Gemert
authors: Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors: M G
authors: MG
authors: van de Vegte-Bolmer
authors: Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors: T
authors: T
authors: Bousema
authors: Medicines for Malaria Venture, Route de Pré-Bois 20, 1215 Geneva 15, Switzerland.
authors: D
authors: D
authors: Leroy
authors: TropIQ Health Sciences, Geert Grooteplein 28, huispost 268, 6525 GA, Nijmegen, The Netherlands Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors: R W
authors: RW
authors: Sauerwein
authors: TropIQ Health Sciences, Geert Grooteplein 28, huispost 268, 6525 GA, Nijmegen, The Netherlands k.dechering@tropiq.nl.
authors: K J
authors: KJ
authors: Dechering
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology; D000962:Antimalarials / Q000302:isolation & purification*; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D010961:Plasmodium / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000962:Antimalarials; D007770:L-Lactate Dehydrogenase
keywords: Plasmodium spp.; drug susceptibility testing; endoperoxides; gametocytes; malaria; transmission