Plasmodium gametocyte inhibition identified from a natural-product-based fragment library.
Fragment-based screening is commonly used to identify compounds with relatively weak but efficient localized binding to protein surfaces. We used mass spectrometry to study fragment-sized three-dimensional natural products. We identified seven securinine-related compounds binding to Plasmodium falciparum 2'-deoxyuridine 5'-triphosphate nucleotidohydrolase (PfdUTPase). Securinine bound allosterically to PfdUTPase, enhancing enzyme activity and inhibiting viability of both P. falciparum gametocyte (sexual) and blood (asexual) stage parasites. Our results provide a new insight into mechanisms that may be applicable to transmission-blocking agents.
Eskitis Institute for Drug Discovery, Griffith University , Brisbane, Queensland, Australia.
Hoan
H
Vu
Catherine
C
Roullier
Marc
M
Campitelli
Katharine R
KR
Trenholme
Donald L
DL
Gardiner
Katherine T
KT
Andrews
Tina
T
Skinner-Adams
Gregory J
GJ
Crowther
Wesley C
WC
Van Voorhis
Ronald J
RJ
Quinn
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry*; D003856:Deoxyuracil Nucleotides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006572:Heterocyclic Compounds, Bridged-Ring / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D007700:Kinetics; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D008018:Life Cycle Stages / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000962:Antimalarials; D001381:Azepines; D001688:Biological Products; D003856:Deoxyuracil Nucleotides; D006572:Heterocyclic Compounds, Bridged-Ring; D007783:Lactones; D010880:Piperidines; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; C027078:deoxyuridine triphosphate; C000785:securinine