title: Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes.
abstract: Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use. In this study, we describe a series of pyrazolopyrimidine- and imidazopyrazine-based compounds that are potent inhibitors of PfCDPK4, which is a calcium-activated Plasmodium protein kinase that is essential for exflagellation of male gametocytes. Thus, PfCDPK4 is essential for the sexual development of Plasmodium parasites and their ability to infect mosquitoes. We demonstrate that two structural features in the ATP-binding site of PfCDPK4 can be exploited in order to obtain potent and selective inhibitors of this enzyme. Furthermore, we demonstrate that pyrazolopyrimidine-based inhibitors that are potent inhibitors of the in vitro activity of PfCDPK4 are also able to block Plasmodium falciparum exflagellation with no observable toxicity to human cells. This medicinal chemistry effort serves as a valuable starting point in the development of safe, transmission-blocking agents for the control of malaria.
authors: Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
authors: Rama Subba Rao
authors: RS
authors: Vidadala
authors: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Kayode K
authors: KK
authors: Ojo
authors: Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
authors: Steven M
authors: SM
authors: Johnson
authors: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors: Zhongsheng
authors: Z
authors: Zhang
authors: Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
authors: Stephen E
authors: SE
authors: Leonard
authors: Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
authors: Arinjay
authors: A
authors: Mitra
authors: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Ryan
authors: R
authors: Choi
authors: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Molly C
authors: MC
authors: Reid
authors: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Katelyn R
authors: KR
authors: Keyloun
authors: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Anna M W
authors: AM
authors: Fox
authors: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors: Mark
authors: M
authors: Kennedy
authors: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors: Tiffany
authors: T
authors: Silver-Brace
authors: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors: Jen C C
authors: JC
authors: Hume
authors: Seattle Biomedical Research Institute, Seattle, WA, USA; Departments of Global Health, University of Washington, Seattle, WA, USA.
authors: Stefan
authors: S
authors: Kappe
authors: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors: Christophe L M J
authors: CL
authors: Verlinde
authors: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors: Erkang
authors: E
authors: Fan
authors: Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors: Ethan A
authors: EA
authors: Merritt
authors: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA; Departments of Global Health, University of Washington, Seattle, WA, USA; Departments of Microbiology, University of Washington, Seattle, WA, USA. Electronic address: wesley@uw.edu.
authors: Wesley C
authors: WC
authors: Van Voorhis
authors: Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA. Electronic address: maly@chem.washington.edu.
authors: Dustin J
authors: DJ
authors: Maly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000635:transmission*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D017386:Sequence Homology, Amino Acid
chemical_list: D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D002118:Calcium
keywords: Exflagellation; PfCDPK1; PfCDPK4; Plasmodium falciparum; Pyrazolopyrimidine