将疟原虫 RNA 三磷酸酶验证为抗疟靶标

Sonia Moliner-Cubel , Noemi Bahamontes-Rosa , Ane Rodriguez-Alejandre , Pamela M. Nassau , Argyrides Argyrou , Anshu Bhardwaja , Rachel C. Buxton , David Calvo-Vicente , Bernadette Mouzon , William McDowell , Alfonso Mendoza-Losana , Maria G. Gomez-Lorenzo
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引用次数: 0

摘要

基于靶点的方法历来被用于寻找新的抗感染分子。靶点选择过程是药物发现的一个关键步骤,它需要确定对建立或维持感染至关重要的靶点,这些靶点应易于抑制,对其人类同源物具有选择性,并适于大规模纯化和高通量筛选。本文介绍的工作验证了恶性疟原虫 mRNA 5' 三磷酸酶 (PfPRT1)--寄生虫核 mRNA 的第一个酶封顶步骤--是开发新型抗疟化合物的候选靶点。PfPRT1 已被确定为隧道金属依赖性 mRNA 5′三磷酸酶家族的成员,在结构上和机制上与人类金属独立的 mRNA 5′三磷酸酶不同。本研究证实了 PfPRT1 的重要性,并开发了用于靶标纯化、酶学评估和靶标参与的分子生物学工具和方法,目的是在未来进行高通量筛选,以发现 PfPRT1 抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Plasmodium RNA triphosphatase validation as antimalarial target

Target-based approaches have traditionally been used in the search for new anti-infective molecules. Target selection process, a critical step in Drug Discovery, identifies targets that are essential to establish or maintain the infection, tractable to be susceptible for inhibition, selective towards their human ortholog and amenable for large scale purification and high throughput screening. The work presented herein validates the Plasmodium falciparum mRNA 5’ triphosphatase (PfPRT1), the first enzymatic step to cap parasite nuclear mRNAs, as a candidate target for the development of new antimalarial compounds. mRNA capping is essential to maintain the integrity and stability of the messengers, allowing their translation. PfPRT1 has been identified as a member of the tunnel, metal dependent mRNA 5′ triphosphatase family which differs structurally and mechanistically from human metal independent mRNA 5′ triphosphatase. In the present study the essentiality of PfPRT1 was confirmed and molecular biology tools and methods for target purification, enzymatic assessment and target engagement were developed, with the goal of running a future high throughput screening to discover PfPRT1 inhibitors.

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来源期刊
CiteScore
7.90
自引率
7.50%
发文量
31
审稿时长
48 days
期刊介绍: The International Journal for Parasitology – Drugs and Drug Resistance is one of a series of specialist, open access journals launched by the International Journal for Parasitology. It publishes the results of original research in the area of anti-parasite drug identification, development and evaluation, and parasite drug resistance. The journal also covers research into natural products as anti-parasitic agents, and bioactive parasite products. Studies can be aimed at unicellular or multicellular parasites of human or veterinary importance.
期刊最新文献
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