期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 144, 期 41, 页码 19070-19077出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c08128
关键词
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资金
- Chinese Scholarship Council
- [ID-23]
This study describes a series of small-molecule inhibitors targeting P. falciparum ATC with low nanomolar binding affinities, selectively binding to a previously unreported allosteric pocket, inhibiting ATC activation.
The discovery and development of new drugs against malaria remain urgent. Aspartate transcarbamoylase (ATC) has been suggested to be a promising target for antimalarial drug development. Here, we describe a series of small-molecule inhibitors of P. falciparum ATC with low nanomolar binding affinities that selectively bind to a previously unreported allosteric pocket, thereby inhibiting ATC activation. We demonstrate that the buried allosteric pocket is located close to the traditional ATC active site and that reported compounds maintain the active site of PfATC in its low substrate affinity/low activity conformation. These compounds inhibit parasite growth in blood stage cultures at single digit micromolar concentrations, whereas limited effects were seen against human normal lymphocytes. To our knowledge, this series represent the first PfATC-specific allosteric inhibitors.
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