Tirbanibulin (KX2-391) analog KX2-361 inhibits botulinum neurotoxin serotype A mediated SNAP-25 cleavage in pre- and post-intoxication models in cells

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-08-21 DOI:10.1002/ddr.22248
Dilara Koc, Kubra Ibis, Peri Besarat, Erden Banoglu, Erkan Kiris
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Abstract

Botulinum neurotoxins (BoNT) inhibit neuroexocytosis, leading to the potentially lethal disease botulism. BoNT serotype A is responsible for most human botulism cases, and there are no approved therapeutics to treat already intoxicated patients. A growing body of research has demonstrated that BoNT/A can escape into the central nervous system, and therefore, identification of BoNT/A inhibitors that can penetrate BBB and neutralize the toxin within intoxicated neurons would be important. We previously identified an FDA-approved, orally bioavailable compound, KX2-391 (Tirbanibulin) that inhibits BoNT/A in motor neuron assays. Recently, a structural analog of KX2-391, KX2-361, has been shown to exhibit good oral bioavailability and cross BBB with high efficiency in mouse experiments. Therefore, in this work, we evaluated the inhibitory effects of KX2-361 against BoNT/A. Toward this goal, we first evaluated the compound for its effects on cell viability in PC12 cells, via MTT assay, and in mouse embryonic stem cell (mESC)-derived motor neurons, with imaging-based assays. Following, we tested KX2-361 in mESC-derived motor neurons intoxicated with BoNT/A holotoxin, and the compound exhibited activity against the toxin in both pre- and post-intoxication conditions. Excitingly, KX2-361 also inhibited BoNT/A enzymatic component (light chain; LC) in PC12 cells transfected with BoNT/A LC. Furthermore, our molecular docking analyses suggested that KX2-361 can directly bind to BoNT/A LC. Medicinal chemistry approaches to develop structural analogs of KX2-361 to increase its efficacy against BoNT/A may provide a critical lead compound with BBB penetration capacity for drug development efforts against BoNT/A intoxication.

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Tirbanibulin(KX2-391)类似物 KX2-361 在细胞中毒前和中毒后模型中抑制 A 血清型肉毒杆菌神经毒素介导的 SNAP-25 分裂。
肉毒杆菌神经毒素(BoNT)会抑制神经外泌,导致潜在的致命疾病肉毒中毒。肉毒杆菌毒素血清型 A 是大多数人类肉毒中毒病例的罪魁祸首,目前还没有获得批准的疗法来治疗已经中毒的病人。越来越多的研究表明,BoNT/A 可以逃逸到中枢神经系统中,因此,找到能够穿透 BBB 并中和中毒神经元中毒素的 BoNT/A 抑制剂非常重要。我们之前发现了一种获得 FDA 批准的口服生物活性化合物 KX2-391(Tirbanibulin),它能在运动神经元实验中抑制 BoNT/A。最近,KX2-391 的结构类似物 KX2-361 在小鼠实验中表现出良好的口服生物利用度,并能高效穿过 BBB。因此,在这项工作中,我们评估了 KX2-361 对 BoNT/A 的抑制作用。为此,我们首先通过 MTT 检测法评估了该化合物对 PC12 细胞和小鼠胚胎干细胞(mESC)衍生运动神经元细胞活力的影响。随后,我们在用 BoNT/A holotoxin 致醉的 mESC 衍生运动神经元中测试了 KX2-361,结果表明该化合物在致醉前和致醉后两种情况下都具有抗毒素活性。令人兴奋的是,KX2-361 还能抑制转染有 BoNT/A LC 的 PC12 细胞中的 BoNT/A 酶成分(轻链;LC)。此外,我们的分子对接分析表明,KX2-361 可直接与 BoNT/A LC 结合。通过药物化学方法开发 KX2-361 的结构类似物以提高其对 BoNT/A 的疗效,可能会为针对 BoNT/A 中毒的药物开发工作提供一种具有 BBB 穿透能力的关键先导化合物。
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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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