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探索自蛋白 LC3B 和 GABARAP 的阿里里丁 - 印度林联体

Alexandria N Leveille¹, Thomas Schwarzrock¹, Hawley Brown¹

¹Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford MA, USA.

bioRxiv : the preprint server for biology

|November 18, 2024

概括

对GW5074的结构活性研究显示,它与自蛋白LC3B和GABARAP有微分子结合亲和关系. 这些发现支持针对性蛋白质降解的进一步探索,等待溶解度和非目标问题的解决.

科学领域:

生物化学生物化学
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

阿里利丁 - 印度林化合物GW5074是与自相关的蛋白质LC3B的被报告的配体.
关于GW5074的结合亲和力及其在自依赖蛋白质降解剂中的效用,存在相互矛盾的文献.

研究的目的:

对GW5074及其类似物进行第一个结构-活性关系 (SAR) 研究.
为了澄清GW5074与LC3B及其对应物GABARAP的结合特性.
评估GW5074衍生物在向蛋白质降解应用中的潜力.

主要方法:

合成和测试18个GW5074对LC3B和GABARAP的类似物.
利用AlphaScreen测试来测量联体结合的竞争性抑制.
采用2D-NMR光谱学来识别GABARAP结合部位.使用2D-NMR光谱学来识别GABARAP结合部位.

主要成果:

GW5074及其类型对LC3B和GABARAP具有中高微分子范围的抑制作用.
2D-NMR确定了GABARAP的结合部位为疏水口袋1,与原生联体相互作用一致.
这项研究确定了GW5074对LC3B和GABARAP的微分子结合亲缘关系.

结论:

GW5074对LC3B和GABARAP具有中度的结合亲和力.
鉴定到的结合性特征要求对向蛋白质降解策略进行进一步的研究.
解决GW5074的非目标效应和不良溶解性对于其治疗潜力至关重要.

关键词:

自自是自的过程.蛋白质与蛋白质的相互作用小分子抑制剂小分子抑制剂结构 - 活动关系结构 - 活动关系

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