摘要
结核分枝杆菌(MTB)是人类肺结核(TB)的主要病原体在,每年造成近二百万人死亡。尽管现有的抗结核药物存在巨大的治疗价值,但仍有几个缺点,例如抗药性的涌现,这主要由漫长的治疗过程中缺乏依从性所引起的。此为了缩短治疗时间和解决与抗生素疗效渐进性丧失的问题,新型有效、作用于在新分子靶点的抗结核分枝杆菌药物亟待开发。结核分枝杆菌编码两种低分子量的酪氨酸磷酸酶(Mptpa和MptpB)是结核发病机制的关键。MptpA干扰吞噬体酸化从而阻碍其成熟,而MptpB破坏宿主信号转导级联反应,引起宿主免疫反应的颠覆。Mptpa和MptpB在宿主病原体相互作用中发挥着重要的作用,这使他们成为TB药物发现有吸引力的目标。本文提供对Mptpa和MptpB特征以及其在结核病发病机制中的作用进行了概括总结。特别是对所有已经开发和研究的抑制剂;包括其结合模式,设计策略,生物活性,主要药效特点以及克服活性化合物较差的成药性努力等方面做了比较详细的总结。
关键词: 抗菌化合物,酶抑制剂,LMW- PTP,结核分枝杆菌,天然化合物,合成的衍生物。
Current Medicinal Chemistry
Title:Mycobacterium tuberculosis Low Molecular Weight Phosphatases (MPtpA and MPtpB): From Biological Insight to Inhibitors
Volume: 22 Issue: 27
Author(s): Luisa Fanzani, Federica Porta, Fiorella Meneghetti, Stefania Villa, Arianna Gelain, Anna Paola Lucarelli and Emilio Parisini
Affiliation:
关键词: 抗菌化合物,酶抑制剂,LMW- PTP,结核分枝杆菌,天然化合物,合成的衍生物。
摘要: Mycobacterium tuberculosis (Mtb), the main aetiological agent of tuberculosis (TB) in humans, is estimated to cause nearly two million deaths every year. Despite their huge therapeutic value, existing antitubercular drugs have several shortcomings, such as for instance the insurgence of drug resistance, which is mostly triggered by lack of compliance during the lengthy treatment. Novel and more effective drugs against Mtb acting on new molecular targets are therefore in demand in order to reduce treatment time and address the severe issue related to the progressive loss of antibiotic efficacy. Mtb encodes for two low molecular weight tyrosine specific phosphatases (MPtpA and MPtpB) that are crucially involved in Mtb pathogenesis. While MPtpA interferes with phagosome acidification blocking its maturation, MPtpB disrupts host signal transduction cascades, causing immune response subversion in the host. The important role played by both MPtpA and MPtpB in host–pathogen interaction makes them appealing targets for TB drug discovery. Here, we provide an exhaustive review of the current knowledge on MPtpA and MPtpB characterization and role in TB pathogenesis. In particular, special emphasis is placed on all class of inhibitors that have been developed and studied to date; their binding mode, design strategies, biological activities, main pharmacophore features as well as the efforts to overcome the poor druggability of their target are summarized in detail.
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Cite this article as:
Luisa Fanzani, Federica Porta, Fiorella Meneghetti, Stefania Villa, Arianna Gelain, Anna Paola Lucarelli and Emilio Parisini , Mycobacterium tuberculosis Low Molecular Weight Phosphatases (MPtpA and MPtpB): From Biological Insight to Inhibitors, Current Medicinal Chemistry 2015; 22 (27) . https://dx.doi.org/10.2174/0929867322666150812150036
DOI https://dx.doi.org/10.2174/0929867322666150812150036 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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