Epitope alteration by small molecules and applications in drug discovery.
Epitope alteration by small molecules and applications in drug discovery.
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DOI：
10.1039/d2sc02819k
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发表时间：
2022-07-13
期刊：
影响因子：
8.4
通讯作者：
中科院分区：
文献类型：
--
作者：
除了共价偶联物外，小分子和抗体通常在药物发现中被分开考虑。我们意外地发现了几个可以抑制或增强抗体-表位相互作用的小分子，这为药物发现和自身抗体的治疗调节开辟了新的可能性。我们首先发现了一种小分子，CRANAD-17，它通过稳定的三联体形成增强了抗体与β淀粉样蛋白（a β）的结合，β淀粉样蛋白是阿尔茨海默病的主要标志之一。接下来，我们发现了几个改变tau和PD-L1蛋白的抗体-表位相互作用的小分子，证明了这种现象的普遍性。本文报道了一种新的配体发现筛选技术——基于表位改变的药物发现筛选平台（SPEED），该平台对抗体和小分子均无标记。将SPEED应用于一种a β抗体，发现了一种小分子GNF5837可以抑制a β聚集，另一种小分子obatoclax可以结合a β斑块，并在AD小鼠脑切片中作为荧光报告基因。我们还发现一个小分子可以改变AD患者血清中a β和自身抗体之间的结合。SPEED揭示了抗体-表位相互作用对小分子扰动的敏感性，将在生物技术和药物发现中有多种应用。基于表位改变的药物发现筛选平台（SPEED）。
Small molecules and antibodies are normally considered separately in drug discovery, except in the case of covalent conjugates. We unexpectedly discovered several small molecules that could inhibit or enhance antibody–epitope interactions which opens new possibilities in drug discovery and therapeutic modulation of auto-antibodies. We first discovered a small molecule, CRANAD-17, that enhanced the binding of an antibody to amyloid beta (Aβ), one of the major hallmarks of Alzheimer's disease, by stable triplex formation. Next, we found several small molecules that altered antibody–epitope interactions of tau and PD-L1 proteins, demonstrating the generality of this phenomenon. We report a new screening technology for ligand discovery, screening platform based on epitope alteration for drug discovery (SPEED), which is label-free for both the antibody and small molecule. SPEED, applied to an Aβ antibody, led to the discovery of a small molecule, GNF5837, that inhibits Aβ aggregation and another, obatoclax, that binds Aβ plaques and can serve as a fluorescent reporter in brain slices of AD mice. We also found a small molecule that altered the binding between Aβ and auto-antibodies from AD patient serum. SPEED reveals the sensitivity of antibody–epitope interactions to perturbation by small molecules and will have multiple applications in biotechnology and drug discovery. A screening platform based on epitope alteration for drug discovery (SPEED).
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影响因子：
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作者：
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通讯作者：
Eisenberg D
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