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深入了解MptpB抑制剂作为治疗耐多药和广泛耐药结核病的关键策略。

An Insight into MptpB Inhibitors as a Key Strategy to Treat MDR and XDRTuberculosis.

作者信息

Jain Madhur, Gollapudi Sirisha, Khatik Gopal L

机构信息

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli, New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh, 226002, India.

出版信息

Curr Pharm Des. 2023;29(8):562-575. doi: 10.2174/1381612829666230308112634.

Abstract

Tuberculosis (TB) is a chronic, air-borne infectious disease caused by Mycobacterium tuberculosis (Mtb), which prominently affects the lungs and usually manifests in other organs. TB is preventable and curable but what makes it challenging is the emergence of resistance to the available treatment options. MDR-continued TB's expansion is one of the world's most pressing and difficult problems. Mtb revives via the reciprocity between Mycobacterium and host signalling pathways. Mtb secretes a virulence component called Mycobacterium tuberculosis protein tyrosine phosphatase (MptpB), which helps to survive against host macrophages. It indicates that targeting secreted virulence factors offers more benefits to circumvent the emergence of resistance. Many effective inhibitors of MptpA and MptpB have been discovered, providing a solid foundation for future research and development. Aside from possessing a structurally unique binding site in the Mtb enzyme, MptpB's minimal resemblance to other human phosphatases provides a broad platform for improving selectivity over host PTPs. We believe that addressing several parts of infection processes in the host and bacteria with combination therapy is the greatest way to reduce treatment burden and medication resistance. We have discussed the recent potent, selective, and efficacious MptpB inhibitors, such as natural and marine-based, isoxazole- linked carboxylic acid-based, oxamic acid-based, and lactone-based inhibitors, as potential strategies for treating TB.

摘要

结核病(TB)是一种由结核分枝杆菌(Mtb)引起的慢性空气传播传染病,主要影响肺部,通常也会在其他器官中表现出来。结核病是可预防和可治愈的,但具有挑战性的是对现有治疗方案出现了耐药性。耐多药结核病的蔓延是世界上最紧迫和最棘手的问题之一。Mtb通过分枝杆菌与宿主信号通路之间的相互作用得以复苏。Mtb分泌一种名为结核分枝杆菌蛋白酪氨酸磷酸酶(MptpB)的毒力成分,它有助于在宿主巨噬细胞中存活。这表明靶向分泌的毒力因子对于规避耐药性的出现更有益处。已经发现了许多有效的MptpA和MptpB抑制剂,为未来的研发奠定了坚实基础。除了在Mtb酶中拥有结构独特的结合位点外,MptpB与其他人类磷酸酶的极小相似性为提高对宿主蛋白酪氨酸磷酸酶(PTP)的选择性提供了广阔平台。我们认为,通过联合疗法针对宿主和细菌感染过程的多个环节进行治疗,是减轻治疗负担和耐药性的最佳方法。我们讨论了近期强效、选择性和有效的MptpB抑制剂,如天然和海洋来源的、异恶唑连接羧酸类、草氨酸类和内酯类抑制剂,作为治疗结核病的潜在策略。

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