securinine and deoxyuridine-triphosphate

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.

Topics: Alkaloids; Antimalarials; Azepines; Biological Products; Deoxyuracil Nucleotides; Dose-Response Relationship, Drug; Heterocyclic Compounds, Bridged-Ring; Kinetics; Lactones; Life Cycle Stages; Piperidines; Plasmodium falciparum; Protozoan Proteins; Recombinant Fusion Proteins; Small Molecule Libraries; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship