Misra Sweta, Valicherla Guru R, Gupta Jyoti, Gayen Jiaur R, Misra-Bhattacharya Shailja
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Parasitology, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India.
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031 (U.P.), India.
Pathog Dis. 2016 Aug;74(6). doi: 10.1093/femspd/ftw072. Epub 2016 Jul 26.
Lymphatic filariasis, a vector-borne neglected tropical disease affects millions of population in tropical and subtropical countries. Vaccine unavailability and emerging drug resistance against standard antifilarial drugs necessitate search of novel drug targets for developing alternate drugs. Recently, UDP-galactopyranose mutases (UGM) have emerged as a promising drug target playing an important role in parasite virulence and survival. This study deals with the cloning and characterization of Brugia malayi UGM and further exploring its antifilarial drug target potential. The recombinant protein was actively involved in conversion of UDP-galactopyranose (substrate) to UDP-galactofuranose (product) revealing Km and Vmax to be ∼51.15 μM and ∼1.27 μM/min, respectively. The purified protein appeared to be decameric in native state and its 3D homology modeling using Aspergillus fumigatus UGM enzyme as template revealed conservation of active site residues. Two specific prokaryotic inhibitors (compounds A and B) of the enzyme inhibited B. malayi UGM enzymatic activity competitively depicting Ki values ∼22.68 and ∼23.0 μM, respectively. These compounds were also active in vitro and in vivo against B. malayi The findings suggest that B. malayi UGM could be a potential antifilarial therapeutic drug target.
淋巴丝虫病是一种由媒介传播的被忽视的热带病，影响着热带和亚热带国家的数百万人。由于无法获得疫苗以及对标准抗丝虫药物出现耐药性，因此有必要寻找新的药物靶点以开发替代药物。最近，尿苷二磷酸半乳糖吡喃糖变位酶（UGM）已成为一个有前景的药物靶点，在寄生虫的毒力和生存中发挥着重要作用。本研究涉及马来布鲁线虫UGM的克隆和特性分析，并进一步探索其作为抗丝虫药物靶点的潜力。重组蛋白积极参与了将尿苷二磷酸半乳糖吡喃糖（底物）转化为尿苷二磷酸半乳糖呋喃糖（产物）的过程，其米氏常数（Km）和约最大反应速度（Vmax）分别为51.15 μM和1.27 μM/分钟。纯化后的蛋白在天然状态下似乎是十聚体，以烟曲霉UGM酶为模板对其进行三维同源建模显示活性位点残基具有保守性。该酶的两种特异性原核抑制剂（化合物A和B）竞争性抑制马来布鲁线虫UGM的酶活性，其抑制常数（Ki）值分别约为22.68和~23.0 μM。这些化合物在体外和体内对马来布鲁线虫也具有活性。研究结果表明，马来布鲁线虫UGM可能是一个潜在的抗丝虫治疗药物靶点。
