Identification of 3-hydroxy-1,2-dimethylpyridine-4(1H)-thione as a metal-binding motif for the inhibition of botulinum neurotoxin A,RSC Medicinal Chemistry

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Identification of 3-hydroxy-1,2-dimethylpyridine-4(1H)-thione as a metal-binding motif for the inhibition of botulinum neurotoxin A
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-11-12 , DOI: 10.1039/d0md00320d
Lucy Lin ₁ , Lewis D Turner ₁ , Peter Šilhár ₁ , Sabine Pellett ₂ , Eric A Johnson ₂ , Kim D Janda ₁

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Botulinum neurotoxin serotype A (BoNT/A) is an important therapeutic target owing to its extremely potent nature, but also has potential use as a biowarfare agent. Currently, no therapeutic exists to reverse the long-lasting paralysis caused by BoNT/A. Herein, we describe the identification of 3-hydroxy-1,2-dimethylpyridine-4(1H)-thione (3,4-HOPTO) as a metal binding warhead for the inhibition of BoNT/A1. An initial screen of 96 metal binding fragments identified three derivatives containing the 3,4-HOPTO scaffold to inhibit the BoNT/A1 light chain (LC) at >95% at 1 mM. Additional screening of a 3,4-HOPTO sub-library identified structure–activity relationships (SARs) between N-substituted 3,4-HOPTO derivatives and the BoNT/A1 LC. Subsequent synthesis was conducted to improve on inhibitory potency – achieving low μM biochemical IC₅₀ values. Representative compounds were evaluated in a cellular-based assay and showed promising μM activity.

中文翻译：

鉴定 3-羟基-1,2-二甲基吡啶-4(1H)-硫酮作为抑制肉毒杆菌神经毒素 A 的金属结合基序

A 型肉毒杆菌神经毒素 (BoNT/A) 因其极其有效的性质而成为重要的治疗靶点，而且也具有作为生物战剂的潜在用途。目前，尚无治疗方法可以逆转 BoNT/A 引起的长期瘫痪。在此，我们描述了 3-羟基-1,2-二甲基吡啶-4(1 H )-硫酮 (3,4-HOPTO) 作为金属结合弹头用于抑制 BoNT/A1 的鉴定。对 96 个金属结合片段的初步筛选鉴定出三种含有 3,4-HOPTO 支架的衍生物，在 1 mM 浓度下可抑制 BoNT/A1 轻链 (LC) >95%。对 3,4-HOPTO 子库的额外筛选确定了N取代的 3,4-HOPTO 衍生物与 BoNT/A1 LC 之间的结构-活性关系 (SAR)。随后进行合成以提高抑制效力 - 实现低 μM 生化 IC ₅₀值。代表性化合物在基于细胞的测定中进行了评估，并显示出有希望的 μM 活性。

更新日期：2021-01-12

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