Plasmodium Gametocyte Inhibition Identified from a Natural-Product-Based Fragment Library

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• 作者：Hoan Vu ; Catherine Roullier ; Marc Campitelli ; Katharine R. Trenholme ; Donald L. Gardiner ; Katherine T. Andrews ; Tina Skinner-Adams ; Gregory J. Crowther ; Wesley C. Van Voorhis ; Ronald J. Quinn
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：December 20, 2013
• 年：2013
• 卷：8
• 期：12
• 页码：2654-2659
• 全文大小：287K
• 年卷期：v.8,no.12(December 20, 2013)
• ISSN：1554-8937

文摘

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鈥?deoxyuridine 5鈥?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.