Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
FEBS Open Bio. 2021 Jul;11(7):1921-1929. doi: 10.1002/2211-5463.13171. Epub 2021 May 29.
Post-translational modifications, especially reversible phosphorylation, are among the most common mechanisms that regulate protein function and biological processes in Plasmodium species. Of the Plasmodium phosphatases, phosphatase of regenerating liver (PfPRL) is secreted and is an essential phosphatase. Here, we expressed PfPRL in a heterologous expression system, and then purified and characterized its phosphatase activity. We found that Novartis_003209, a previously identified inhibitor, inhibited the PfPRL phosphatase activity of recombinant PfPRL and blocked in vitro parasite growth in a dose-dependent manner. Further, in silico docking analysis of Novartis_003209 with all four P. falciparum tyrosine phosphatases (PTP) demonstrated that Novartis_003209 is a Plasmodium PTP inhibitor. Overall, our results identify a scaffold as a potential starting point to design a PTP-specific inhibitor.
在疟原虫属中，翻译后修饰（尤其是可逆磷酸化）是调节蛋白质功能和生物过程的最常见机制之一。在疟原虫磷酸酶中，肝再生磷酸酶（PfPRL）是一种分泌型必需磷酸酶。本研究在异源表达系统中表达 PfPRL，然后纯化并鉴定其磷酸酶活性。结果发现，先前鉴定的抑制剂 Novartis_003209 可抑制重组 PfPRL 的磷酸酶活性，并呈剂量依赖性抑制寄生虫在体外生长。此外，Novartis_003209 与所有四种恶性疟原虫酪氨酸磷酸酶（PTP）的计算机对接分析表明，Novartis_003209 是一种疟原虫 PTP 抑制剂。总之，本研究结果确定了一种支架作为设计 PTP 特异性抑制剂的潜在起点。
