Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / chemistry
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Alkaloids / isolation & purification
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Alkaloids / pharmacology
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Antimalarials / chemistry
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Antimalarials / isolation & purification
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Antimalarials / pharmacology*
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Azepines / chemistry
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Azepines / isolation & purification
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Azepines / pharmacology
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Biological Products / chemistry*
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Deoxyuracil Nucleotides / antagonists & inhibitors
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Deoxyuracil Nucleotides / chemistry
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Deoxyuracil Nucleotides / metabolism
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Dose-Response Relationship, Drug
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Heterocyclic Compounds, Bridged-Ring / chemistry
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Heterocyclic Compounds, Bridged-Ring / isolation & purification
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Heterocyclic Compounds, Bridged-Ring / pharmacology
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Kinetics
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Lactones / chemistry
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Lactones / isolation & purification
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Lactones / pharmacology
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Life Cycle Stages / drug effects*
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Life Cycle Stages / physiology
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Piperidines / chemistry
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Piperidines / isolation & purification
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Piperidines / pharmacology
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Plasmodium falciparum / drug effects*
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Plasmodium falciparum / enzymology
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Plasmodium falciparum / growth & development
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / chemistry
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Protozoan Proteins / metabolism
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Small Molecule Libraries / chemistry*
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
Substances
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Alkaloids
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Antimalarials
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Azepines
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Biological Products
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Deoxyuracil Nucleotides
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Heterocyclic Compounds, Bridged-Ring
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Lactones
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Piperidines
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Protozoan Proteins
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Recombinant Fusion Proteins
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Small Molecule Libraries
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deoxyuridine triphosphate
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securinine