美国斯坦福大学Axel T. Brunger、Ying Lai和美国德克萨斯大学MD安德森癌症中心Burton F. Dickey以及德国乌尔姆大学Manfred Frick及其研究团队合作取得最新进展。他们提出了碳氢化合物固定肽抑制钙触发的分泌。这一研究成果于2022年3月23日发表在国际顶尖学术期刊《自然》上。
他们设计了一种碳氢化合物固定肽，它通过干扰神经元 SNARE 复合物和突触结合蛋白-1 的 Ca2+ 结合 C2B 结构域之间的所谓初级界面来特异性破坏 Ca2+ 触发的膜融合。在具有这些神经元突触蛋白或其气道同源物 synaptotagmin-2 以及 Munc13-2 和 Munc18-2 的重组系统中，固定肽在生理 Ca2+ 浓度下强烈抑制 Ca2+ 触发的融合。细胞穿透肽与固定肽的结合导致有效递送到培养的人气道上皮细胞和小鼠气道上皮细胞中，在这两个系统中它显著和特异性地减少了受刺激的粘蛋白分泌，并大大减弱了小鼠气道的粘液阻塞。总之，破坏 Ca2+ 引发的膜融合的肽可能能够对粘蛋白分泌途径进行治疗性调节。
研究人员表示，由 Ca2+ 触发的膜融合由一组保守的蛋白质协调，以介导突触神经递质释放、粘蛋白分泌和其他受调节的胞吐过程。对于神经递质释放，Ca2+ 敏感性是通过 Ca2+ 传感器突触结合蛋白和 SNARE 复合物之间的相互作用引入的，序列保守性和功能研究表明，这种机制对于粘蛋白分泌也是保守性的。药物破坏 Ca2+ 触发的膜融合对粘液分泌过多具有治疗价值，因为它是呼吸道病毒感染、哮喘、慢性阻塞性肺病和囊性纤维化的病理生理学中气道阻塞的主要原因。
附：英文原文
Title: Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides
Author: Lai, Ying, Fois, Giorgio, Flores, Jose R., Tuvim, Michael J., Zhou, Qiangjun, Yang, Kailu, Leitz, Jeremy, Peters, John, Zhang, Yunxiang, Pfuetzner, Richard A., Esquivies, Luis, Jones, Philip, Frick, Manfred, Dickey, Burton F., Brunger, Axel T.
Issue&Volume: 2022-03-23
Abstract: Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes1,2,3,4. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex5, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion6. Disruption of Ca2+-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis7,8,9,10,11. Here we designed a hydrocarbon-stapled peptide that specifically disrupts Ca2+-triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and the Ca2+-binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMP8, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca2+-triggered fusion at physiological Ca2+ concentrations. Conjugation of cell-penetrating peptides to the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca2+-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.
DOI: 10.1038/s41586-022-04543-1
Source: https://www.nature.com/articles/s41586-022-04543-1
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
