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结核靶点的新态势:一种药物化学方法

The Emerging Landscape of Tubercular Targets: A Medicinal Chemistry Approach.

作者信息

Shaik Baji Baba, Moodley Kimeshni, Ghumran Safiyah, Bala Muhammad D, Singh Parvesh, Karpoormath Rajshekhar

机构信息

Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville), Durban, South Africa.

School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa.

出版信息

Med Res Rev. 2025 Jul;45(4):1077-1125. doi: 10.1002/med.22100. Epub 2025 Feb 6.

Abstract

Antitubercular drug discovery progress in the last decade, especially research on the biological function, target inhibition and diagnosis of tuberculosis (TB) diagnosis has considerably advanced. The application of target-based drug discovery techniques have become a more powerful tool for medicinal chemists in developing new therapeutic strategies, such as its application in the identification/validation of new targets, new leads, and drug candidates with optimized efficacy. This has been further evidenced by the recent approval of delamanid and bedaquiline for the treatment of MDR-TB and XDR-TB, respectively. While a TB drug pipeline has shown great development, high attrition rates must constantly replenish the pipeline with high-quality leads acting through the inhibition of new targets. This review provides a critical analysis of the approaches used to advance hit compounds into viable lead candidates as well as the possible influence of new targets on drug development in the near future. Finally, we concluded with the present challenges that are faced in TB drug development.

摘要

过去十年中抗结核药物研发取得了进展,尤其是在结核病的生物学功能、靶点抑制及诊断方面的研究有了显著进步。基于靶点的药物研发技术的应用,已成为药物化学家制定新治疗策略的更强大工具,比如其在新靶点、新先导化合物及具有优化疗效的候选药物的鉴定/验证中的应用。德拉马尼和贝达喹啉分别被批准用于治疗耐多药结核病和广泛耐药结核病,进一步证明了这一点。尽管结核病药物研发线已取得巨大进展,但高淘汰率仍须不断用通过抑制新靶点起作用的高质量先导化合物来充实研发线。本综述对将活性化合物推进为可行的先导候选物所采用的方法,以及新靶点在不久的将来对药物研发可能产生的影响进行了批判性分析。最后,我们总结了结核病药物研发目前面临的挑战。

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