Humanin (HN), a 24-amino acid bioactive peptide, has been shown to increase cell survival of neurons after exposure to Aβ and NMDA-induced toxicity and thus could be beneficial in the treatment of Alzheimer’s disease (AD). The neuroprotection by HN is reported to be primarily through its agonist binding properties to the gp130 receptor. However, the peptidic nature of HN presents challenges in its development as a therapeutic for AD. We report here for the first time the elucidation of the binding site of Humanin (HN) peptide to the gp130 receptor extracellular domain through modeling and the synthesis of small molecule mimetics that interact with the HN binding site on the gp130 receptor and provide protection against NMDA-induced neurotoxicity in primary hippocampal neurons. A brain permeable small molecule mimetic was identified through exploratory medicinal chemistry using microfluidic flow chemistry to facilitate the synthesis of new analogues for screening and SAR optimization.

中文翻译：

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Humanin 肽的小分子模拟物作为调节 NMDA 诱导的神经毒性的候选物

Humanin (HN) 是一种 24 个氨基酸的生物活性肽，已被证明可以在暴露于 Aβ 和 NMDA 诱导的毒性后增加神经元的细胞存活率，因此可能有益于治疗阿尔茨海默病 (AD)。据报道，HN 的神经保护作用主要是通过其激动剂与 gp130 受体的结合特性。然而，HN 的肽性质对其作为 AD 治疗剂的发展提出了挑战。我们在此首次报告通过建模和合成与 gp130 受体上的 HN 结合位点相互作用并提供针对 NMDA 的保护的小分子模拟物，阐明了 Humanin (HN) 肽与 gp130 受体胞外域的结合位点-在原代海马神经元中诱导的神经毒性。