Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?,BioEssays

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Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?
BioEssays ( IF 3.2 ) Pub Date : 2020-08-09 , DOI: 10.1002/bies.202000011
Steven D Buckingham _{1,

2} , Harry-Jack Mann ₂ , Olivia K Hearnden ₂ , David B Sattelle ₂

Affiliation

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, L‐glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy.

中文翻译：

将药物靶标转化为候选药物：神经药物发现的新范式？

开发新的疾病治疗方法的传统范式主要涉及发现新的药物靶点，或者为旧的靶点寻找新的、改进的药物。然而，仅在无脊椎动物中发现的离子通道提供了一种全新范式的潜力，其中可以重新设计已建立的药物靶标以用作新的候选治疗剂。脊椎动物基因组中不存在无脊椎动物的 L-谷氨酸门控氯离子通道 (GluCls)，这提供了将这种外源性、抑制性 L-谷氨酸受体引入脊椎动物神经元回路的机会，作为研究神经网络的工具，或候选疗法。癫痫发作可能涉及 L-谷氨酸诱导的过度兴奋和毒性。变体 GluCls，具有对 L-谷氨酸的抑制反应，当被设计成人类神经元时，可能会抵消过量 L-谷氨酸的兴奋性毒性作用。在回顾最近对模式生物的研究时，似乎这种方法可能为开发癫痫候选疗法提供新的范例。

更新日期：2020-08-26

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