Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents.
Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents.
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DOI：
10.3389/fcimb.2020.605662
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发表时间：
2020
影响因子：
5.7
通讯作者：
Strauss E
中科院分区：
文献类型：
--
作者：
Butman HS;Kotzé TJ;Dowd CS;Strauss E
尽管进行了数十年的专门研究，但仍然迫切需要抗结核病 (TB) 的新药。目前的疗法已经有几代人的历史并且存在问题。对这些现有疗法的抵抗导致患有难以或不可能治疗的疾病的患者的负担不断增加。因此，迫切需要具有新作用机制的新型化学实体。人们早就知道辅酶 A (CoA) 的生物合成对于结核病病原体结核分枝杆菌 (Mtb) 至关重要。该途径已通过体外和体内开创性研究得到遗传验证。在 Mtb 中，CoA 生物合成途径由九种酶组成：其中四种用于从 L-天冬氨酸和 α-酮异戊酸合成泛酸 (Pan)；四种用于从 L-天冬氨酸和 α-酮异戊酸合成泛酸 (Pan)； 5 从 Pan 和泛酰乙胺 (PantSH) 合成 CoA。本综述收集了有关 CoA 途径中每种酶的结构/机制、抑制剂和脆弱性的文献报告。除了传统的单一酶抑制之外，CoA 途径还提供了一种抗代谢策略作为一种有前途的替代方案。在这篇综述中，我们对最佳靶点进行了评估，从而评估了哪些 CoA 途径酶为抗结核药物发现提供了最佳机会。
Despite decades of dedicated research, there remains a dire need for new drugs against tuberculosis (TB). Current therapies are generations old and problematic. Resistance to these existing therapies results in an ever-increasing burden of patients with disease that is difficult or impossible to treat. Novel chemical entities with new mechanisms of action are therefore earnestly required. The biosynthesis of coenzyme A (CoA) has long been known to be essential in Mycobacterium tuberculosis (Mtb), the causative agent of TB. The pathway has been genetically validated by seminal studies in vitro and in vivo. In Mtb, the CoA biosynthetic pathway is comprised of nine enzymes: four to synthesize pantothenate (Pan) from l-aspartate and α-ketoisovalerate; five to synthesize CoA from Pan and pantetheine (PantSH). This review gathers literature reports on the structure/mechanism, inhibitors, and vulnerability of each enzyme in the CoA pathway. In addition to traditional inhibition of a single enzyme, the CoA pathway offers an antimetabolite strategy as a promising alternative. In this review, we provide our assessment of what appear to be the best targets, and, thus, which CoA pathway enzymes present the best opportunities for antitubercular drug discovery moving forward.
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DOI：
10.1107/s1744309104028040
发表时间：
2005-01-01
影响因子：
0.9
作者：
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通讯作者：
Abell, Chris