Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive 0741, La Jolla, California 92093, USA.
- Erika L. Flannery &
- Elizabeth A. Winzeler
California Institute for Biomedical Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, USA.
- Arnab K. Chatterjee
Competing interests statement
E.A.W. holds a research grant from the Wellcome Trust which is shared with the Novartis Institute for Tropical Diseases, Singapore, as the primary recipient. A.K.C. is an author on patents for compounds described in this manuscript. E.L.F. declares no competing interests.
Erika L. Flannery
Erika L. Flannery is a postdoctoral fellow in the laboratory of Elizabeth A. Winzeler at the University of California San Diego School of Medicine, USA. She received her B.Sc. in cellular and molecular biology in 2004 from the University of Michigan, Ann Arbor, Michigan, USA. She earned her M.P.H. in hospital and molecular epidemiology and her Ph.D. in epidemiology from the University of Michigan School of Public Health, USA, where she studied horizontal gene transfer in the laboratory of Harry L. T. Mobley and host colonization rates with multidrug-resistant organisms with Betsy Foxman and Lona Mody. She is currently a Ruth L. Kirschstein National Research Service Award (NRSA) recipient. Her research interests include combining genomics and epidemiology to effectively identify pathogen factors that contribute to antimalarial drug resistance in Plasmodium species.
Arnab K. Chatterjee
Arnab K. Chatterjee completed a B.A. in chemistry and a minor in business from Northwestern University, Evanston, Illinois, USA, in 1997 and joined the California Institute of Technology, Pasadena, California, USA, in October 1998 to carry out his doctoral research in the laboratory of Robert H. Grubbs in the Division of Chemistry and Chemical Engineering. On completion of his doctoral research in September 2002, he joined the Genomics Institute of the Novartis Research Foundation, San Diego, California, USA, as a principal investigator in the chemistry department. Since May 2012, he has been responsible for setting up and leading the chemistry group at the new California Institute of Biomedical Research in La Jolla, California, USA, working across a wide range of disease areas. His research interests include the application of novel synthetic methods to expedite structural diversification in medicinal chemistry and cell-based lead optimization.
Elizabeth A. Winzeler
Elizabeth A. Winzeler received her B.A. in natural sciences and art from Lewis and Clark College, Portland, Oregan, USA, in 1984. She obtained a Ph.D. in 1996 from the Department of Developmental Biology at the Stanford University School of Medicine, California, USA. This was followed by a postdoctoral fellowship in the Department of Biochemistry. In 1999, she moved to San Diego to take a joint appointment at the Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF), San Diego, California, USA. At GNF she developed a malaria drug discovery programme and screening methods that have resulted in the identification of several novel antimalarial chemotypes. She recently moved to the University of California San Diego School of Medicine, USA, where she is a professor in the Department of Pediatrics.
An absence of the local transmission of malaria.
The complete removal of malaria parasites so that there is no transmission worldwide.
- Radical cure
A treatment that eliminates the hypnozoite form of the parasite and thus prevents relapse from Plasmodium vivax or Plasmodium ovale infections.
The dormant liver-stage forms of the parasite that develop when some Plasmodium vivax and Plasmodium ovale sporozoites invade hepatocytes. These hypnozoites do not replicate but can become activated weeks, months or years later, resulting in a blood-stage infection.
- Single exposure, radical cure and prophylaxis (SERCaP).
A treatment that would only need to be administered in one dose and that would eliminate blood-stage parasites (alleviating the symptoms of malaria) and kill hypnozoites (preventing a new infection from developing).
- Target product profile
A set of guidelines that describes the ideal product. For antimalarial drugs, it might include pharmacokinetic and pharmocodynamic parameters, oral bioavailability, cost, potency and activity against different life cycle stages.
The fixed part of a lead molecule on which chemical functional groups are substituted or exchanged.
- Cheminformatic analysis
Computational analysis using systematic or common chemical names; used to group scaffold families and to discover known activities, toxicities and sometimes targets.
- Structure–activity relationships
(SARs). The relationships between the chemical structures of molecules and their biological activities. The analysis of SARs allows scientists to identify the chemical groups that are responsible for a compound's biological activity.
- Lead compound
This is a chemical compound often discovered in a screen that has pharmacological or biological activity. Its chemical structure is used as a starting point for chemical modifications that improve potency, selectivity or pharmacokinetic parameters.
The infectious parasites that are released when blood-stage schizonts rupture. The merozoites can bind to and invade erythrocytes in a matter of seconds.
Molecules that are structurally equivalent but are mirror images of one another and therefore not superimposable. It is common for one enantiomer of a drug to have more activity than the other.
- Standard membrane-feeding assay
An assay used to determine if a blood culture contains gametocytes that are infectious to mosquitoes. In the assay, mosquitoes feed on human blood that is infected with Plasmodium falciparum parasites and covered with parafilm.
- Causal prophylaxis
The prevention of a blood-stage infection by a therapeutic compound that prevents sporozoites from invading or developing within the liver.
The motile parasite forms that develop from zygotes. Ookinetes are tetraploid as a result of meiosis in the zygote and develop into oocysts on the midgut wall.
- High-content imaging
Automated microscopy that collects images of cellular monolayers stained with antibodies. Computer algorithms are then used to automatically identify features such as number of cells, number of cells in mitosis, size of cells or aberrant shape.
The sexual stages of parasites that develop from asexual parasites and that differentiate into gametes in the mosquito. They are thus the parasite forms responsible for transmission.
The motile infectious forms of the parasite that are transmitted from the mosquito to the human, where they migrate from the dermis to a blood vessel and eventually invade a liver cell.
A malaria parasite that has completed the process of DNA replication and syncytial nuclear division but that is still contained within a single red blood cell or hepatocyte.